cEGF, or complement Clr-like EGF, domains have six conserved cysteine residues disulfide-bonded into the characteristic pattern 'ababcc'. They are found in blood coagulation proteins such as fibrillin, Clr and Cls, thrombomodulin, and the LDL receptor. The core fold of the EGF domain consists of two small β-hairpins packed against each other. Two major structural variants have been identified based on the structural context of the C-terminal cysteine residue of disulfide 'c' in the C-terminal hairpin: hEGFs and cEGFs []. In cEGFs the C-terminal thiol resides on the C-terminal β-sheet, resulting in long loop-lengths between the cysteine residues of disulfide 'c', typically C[10+]XC. These longer loop-lengths may have arisen by selective cysteine loss from a four-disulfide EGF template such as laminin or integrin. Tandem cEGF domains have five linking residues between terminal cysteines of adjacent domains. cEGF domains may or may not bind calcium in the linker region. cEGF domains with the consensus motif CXN4X[F,Y]XCXC are hydroxylated exclusively on the asparagine residue.
Pvs25 and Pvs28 are expressed on the surface of ookinetes from several species of Plasmodium. These proteins are potential candidates for vaccine and induce antibodies that block the infectivity of Plasmodium vivax in immunised animals []. The structure of these protein shows they are composed of four EGF domains [].
This entry represents the laminin-type EGF-like domain (LE) found in Laminin subunit gamma-1 and Netrin-1 from Homo sapiens and Mus musculus. Laminins are the major noncollagenous components of basement membranes that mediate cell adhesion, growth migration, and differentiation [, ]. They are composed of distinct but related alpha, beta and gamma chains that form a cross-shaped molecule consisting of a long arm and three short globular arms. The long arm has a coiled coil structure contributed by all three chains and cross-linked by interchain disulphide bonds [, ]. Beside the different types of globular domains each subunit contains, in its first half, consecutive repeats of about 60 amino acids in length that include eight conserved cysteines []. The tertiary structure of this domain is remotely similar in its N-terminal to that of the EGF-like module [, ](see ). The number of copies of the LE domain in the different forms of laminins is highly variable; from 3 up to 22 copies have been found.A schematic representation of the topology of the four disulphide bonds in the LE domain is shown below.+-------------------++-|-----------+ | +--------+ +-----------------+| | | | | | | |xxCxCxxxxxxxxxxxCxxxxxxxCxxCxxxxxGxxCxxCxxgaagxxxxxxxxxxxCxxsssssssssssssssssssssssssssssssssss'C': conserved cysteine involved in a disulphide bond'a': conserved aromatic residue'G': conserved glycine (lower case = less conserved)'s': region similar to the EGF-like domainLong consecutive arrays of LE domains in laminins form rod-like elements of limited flexibility [], which determine the spacing in the formation of laminin networks of basement membranes [].Netrins control guidance of the central nervous system commissural axons and peripheral motor axons [, , , ]. This protein also serves as a survival factor via its association with its receptors which prevent the initiation of apoptosis, thus being involved in tumorigenesis [, ].
This domain is predominantly found in osteonectin and follistatin. They adopt an EGF-like structure [, ]. Follistatin is involved in diverse activities from embryonic development to cell secretion.
This EGF-like domain is found at the C terminus of the malaria parasite MSP1 protein. MSP1 is the merozoite surface protein 1. This domain is part of the C-terminal fragment that is proteolytically processed from the the rest of the protein and is left attached to the surface of the invading parasite [].
The mammalian ligands that bind the EGF receptor (EGFR) include EGF, transforming growth factor-alpha (TGFalpha), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin (AR), betacellulin (BTC), epiregulin (EPR), and epigen. Each contains one or more copies of the EGF repeat. The EGF domain includes six cysteine residues, which have been shown (in EGF) to be involved in disulphide bonds. The main structure is a two-stranded β-sheet followed by a loop to a C-terminal short two-stranded sheet. Subdomains between the conserved cysteines vary in length.Interestingly, this entry also includes some epidermal growth factor-like proteins secreted from virus, including pro-vaccinia growth factor from Vaccinia virus [].
This family includes RalBP1-associated Eps domain-containing protein 1 (REPS1). REPS1 may coordinate the cellular actions of activated EGF receptors and Ral-GTPases []. It is involved in endocytosis [, ].
Glycosyltransferase 61 family members are further processed into a mature form. Proteins in this family includes O-linked-mannose beta-1,4-N-acetylglucosaminyltransferase 2 (POMGnT2, also known as EOGTL) []and EGF domain-specific O-linked N-acetylglucosamine transferase (EOGT) []. This entry also includes plant beta-(1,2)-xylosyltransferase [].
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF)has been shown [, , , ]to be present, in a moreor less conserved form, in a large number of other, mostly animal proteins. The list of proteins currently known tocontain one or more copiesof an EGF-like pattern is large and varied. The functional significance of EGF domains inwhat appear to be unrelated proteins is not yet clear. However, a common feature is that these repeats are found inthe extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandinG/H synthase). The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved in disulphidebonds. The main structure is a two-stranded β-sheet followed by a loop to a C-terminal short two-stranded sheet.Subdomains between the conserved cysteines vary in length.This entry contains EGF domains found in a variety of extracellular and membrane proteins
This entry represents a group of invertebrate proteins, including Gurken/Spitz from Drosophila melanogaster. They are TGFalpha-like protein that interacts with EGF (epidermal growth factor) receptor. Gurken plays an important role in defining the egg anterior-posterior and dorsal-ventral axes []. Spitz is required for photoreceptor determination in the Drosophila eye []. This entry also includes a myrmicitoxin from Manica rubida (European giant red ant) [].
MVB12A (also known as CFBP) and MVB12B are subunits of the ESCRT-I complex, which mediates the sorting of ubiquitinated cargo protein from the plasma membrane to the endosomal vesicle [, ]. MVB12A plays a key role in the ligand-mediated internalization and down-regulation of the EGF receptor [].
MVB12A (also known as CFBP) and MVB12B are subunits of the ESCRT-I complex, which mediates the sorting of ubiquitinated cargo protein from the plasma membrane to the endosomal vesicle [, ]. MVB12A plays a key role in the ligand-mediated internalization and down-regulation of the EGF receptor [].
This entry represents a short domain found the matrilin (cartilage matrix) proteins. It forms a coiled coil structure and contains a single cysteine residue at its start which is likely to form a di-sulphide bridge with a corresponding cysteine in an upstream EGF domain, thereby spanning the VWA domain of the protein ().This domain is likely to be responsible for protein trimerisation [, ].
This entry represents the C-terminal cytoplasmic domain of vertebrate neural chondroitin sulphate proteoglycans that contain EGF modules. Evidence has been accumulated to support the idea that neural proteoglycans are involved in various cellular events including mitogenesis, differentiation, axonal outgrowth and synaptogenesis []. This domain contains a number of potential sites of phosphorylation by protein kinase C [].
This entry represents a short domain found the matrilin (cartilage matrix) proteins. It forms a coiled coil structure and contains a single cysteine residue at its start which is likely to form a di-sulphide bridge with a corresponding cysteine in an upstream EGF domain, thereby spanning the VWA domain of the protein ().This domain is likely to be responsible for protein trimerisation [, ].
This is the I-EGF domain 1 found in several integrin beta subunits. Structural analysis revealed the presence of four integrin epidermal growth factor-like (I-EGF) domains in integrin beta []. EGF1 lacks one disulfide (C2-C4) relative to the integrin EGF 2, 3, and 4 domains; this allows the C-terminal end of EGF1 to flex remarkably relative to its N-terminal end [].
SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking []. This entry represents the PX domain of SNX16.
This group of plasma glycoproteins includes coagulation factors VII, IX, and X, and proteins C and Z, which belong to MEROPS peptidase family S1, subfamily S1A (chymotrypsin, clan PA(S)). All but protein Z are peptidases and are involved in blood coagulation. The precursors contain a signal sequence, propeptide, Gla domain, two EGF domains (although sometimes only one is detected by Pfam), and a trypsin domain. Except for protein Z, they are further cleaved between the second EGF domain and the trypsin domain into light and heavy chains, which are connected by a disulphide bond. Glutamic acid residues in the Gla domain undergo vitamin K-dependent carboxylation, allowing this region to bind calcium and membrane phospholipid []. The propeptide region is important in providing a recognition site for the gamma-carboxylase []. Typically one aspartic acid residue in the light chain is post-translationally modified to erythro-beta-hydroxyaspartic acid [, ].
RIN1, a member of the RIN (AKA Ras interaction/interference) family, have multifunctional domains including SH2 and proline-rich (PR) domains in the N-terminal region, and RIN-family homology (RH), VPS9 and Ras-association (RA) domains in the C-terminal region. RIN proteins function as Rab5-GEFs []. Previous studies showed that RIN1 interacts with EGF receptors via its SH2 domain and regulates trafficking and degradation of EGF receptors via its interaction with STAM, indicating a vital role for RIN1 in regulating endosomal trafficking of receptor tyrosine kinases (RTKs) []. RIN1 was first identified as a Ras-binding protein that suppresses the activated RAS2 allele in S. cerevisiae. RIN1 binds to the activated Ras through its carboxyl-terminal domain and this Ras-binding domain also binds to 14-3-3 proteins as Raf-1 does [].The SH2 domain of RIN1 are thought to interact with the phosphotyrosine-containing proteins, but the physiological partners for this domain are unknown. The proline-rich domain in RIN1 is similar to the consensus SH3 binding regions.
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF)has been shown [, , , ]to be present, in a moreor less conserved form, in a large number of other, mostly animal proteins. The list of proteins currently known tocontain one or more copies of an EGF-like pattern is large and varied. The functional significance of EGF domains inwhat appear to be unrelated proteins is not yet clear. However, a common feature is that these repeats are found inthe extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandinG/H synthase). The EGF domain includes six cysteine residues which have been shown (in EGF) to be involved in disulphidebonds. The main structure is a two-stranded β-sheet followed by a loop to a C-terminal short two-stranded sheet.Subdomains between the conserved cysteines vary in length.This entry represents a conserved site in the EGF-like domain.
Sorting nexin-5 (SNX5) belongs to the sorting nexin family, which contains a conserved PX (phox homology) domain that is responsible for binding to specific phosphoinositides []. SNX5 also contains a BAR domain that is C terminus to the PX domain. Besides being involved in several stages of intracellular trafficking, SNX5 also plays a role in macropinocytosis and in the internalisation of EGFR after EGF stimulation [, ].
This is a family of conserved proteins representing the enzyme responsible for adding O-fucose to EGF (epidermal growth factor-like) repeats. Six highly conserved cysteines are present as well as a DXD-like motif (ERD), conserved in mammals, Drosophila, and Caenorhabditis elegans. Both features are characteristic of several glycosyltransferase families. The enzyme is a membrane-bound protein released by proteolysis and, as for most glycosyltransferases, is strongly activated by manganese [].
Receptor tyrosine kinases (RTKs) are transmembrane receptors thathave intrinsic, cytoplasmic tyrosine kinase activity. Juxtamembrane regions in RTKs have been shown to play important regulatory functions. Their kinase activity is generally autoinhibited by its JX domain in the absence of ligand-stimulated tyrosine phosphorylation, due to the inhibitory Tyr phosphorylation sites found in the JX domain []. This superfamily represents the JX domain of the EGF receptor [].
This domain adopts a fold similar to other EGF domains, with a flat major and a twisted minor beta sheet. Disulphide pairing, however, is not of the usual 1-3, 2-4, 5-6 type; rather 1-2, 3-4, 5-6 pairing is found. Its extended major sheet (strands beta-2 and beta-3 and the connecting loop) projects into thrombin's active site groove. This domain is required for interaction of thrombomodulin with thrombin, and subsequent activation of protein-C [].
Ligands of the Delta/Serrate/lag-2 (DSL) family and their receptors, members ofthe lin-12/Notch family, mediate cell-cell interactions that specify cell fate in invertebrates and vertebrates. In Caenorhabditis elegans, two DSL genes, lag-2 and apx-1,influence different cell fate decisions during development []. Molecular interaction between Notch and Serrate, another EGF-homologous transmembrane protein containing a region of striking similarity to Delta, has been shown and the same two EGF repeats of Notch may also constitute a Serrate binding domain [, ].
PACSIN2 (protein kinase C and casein kinase substrate in neurons protein 2, also known as Syndapin-2) belongs to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain []. They are cytoplasmic phosphoproteins that play a role in vesicle formation andtransport []. PACSIN2 interacts with several proteins such as Rac1, dynamin, Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP), and synaptojanin via its C-terminal Src homology 3 (SH3) domain []. PACSIN2 negatively regulates the EGF (epidermal growth factor) receptor activation and signaling [, ]. It plays an important role in caveolae membrane sculpting [].
Fibulins area family of ECM glycoproteins characterized by a fibulin-type C-terminal domain preceded by tandem calcium-binding epidermal growth factor (EGF)-like modules. They are involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. There are five fibulins, which can be classified into two subgroups. Fibulin-1 and -2 constitute one subgroup. These fibulins are larger than the others due to the presence of a higher number of EGF modules and an extra domain with three anaphylatoxin modules []. Members of the second subgroup, fibulin-3, -4, and -5, are similarly small in size and highly homologous to one another in modular structure. They consist of a modified cbEGF domain at the N terminus followed by five tandem cbEGF modules and the fibulin-type C-terminal region.EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1, also known as Fibulin-3) binds EGFR, the EGF receptor, inducing EGFR autophosphorylation and the activation of downstream signalling pathways []. It promotes glioma growth and resistance through a novel paracrine regulation of Notch signalling []and may function as a negative regulator of chondrocyte differentiation [].
The Notch signalling pathway is a conserved intercellular signalling mechanism that is essential for proper embryonic development in numerous metazoan organisms []. Members of the Notch gene family encode transmembrane (TM) receptors that are critical for various cell-fate decisions. Multiple ligands that activate Notch and related receptors have been identified, including the Delta and Serrate proteins in Drosophila, and Jagged, the vertebrate orthologue of Serrate [].Members of the Jagged/Serrate group are single-pass TM proteins. They possess a large extracellular region that contains a highly conserved disulphide-rich Delta/Serrate/LAG-2 (DSL) domain, and a variable number of EGF repeats. The cytoplasmic tail region is relatively short (100-150 amino acids) and, following proteolytic cleavage, may translocate to the nucleus to mediate nuclear signalling events [].Defects in Jagged have been shown to result in Alagille syndrome, an autosomal dominant disorder that results in a paucity of intrahepatic bile ducts [].This entry represents the Jagged/Serrate protein family.
This SAM (sterile alpha motif) domain repeat 2 of ANKS1 (also known as AIDA-1) is a protein-protein interaction domain.Proteins contain this domain include ANKS1A (also known as Odin) and ANKS1B (also known as AIDA-1 or EB-1). ANKS1A modulates EGF receptor recycling and stability []. ANKS1B may participate in the regulation of nucleoplasmic coilin protein interactions []. Structurally, ANKS1 consist of N-terminal ankyrin motifs followed by two tandem sterile alpha motif (SAM) domains and a carboxyl phosphotyrosine binding (PTB) domain []. SAM domains of ANKS1 can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor []. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. The second SAM domain may decouple from the first SAM domain to facilitate translocation of AIDA-1 to the nucleus [].
This SAM (sterile alpha motif) domain repeat 1 of ANKS1 (also known as AIDA-1) is a protein-protein interaction domain.Proteins contain this domain include ANKS1A (also known as Odin) and ANKS1B (also known as AIDA-1 or EB-1). ANKS1A modulates EGF receptor recycling and stability []. ANKS1B may participate in the regulation of nucleoplasmic coilin protein interactions []. Structurally, ANKS1 consist of N-terminal ankyrin motifs followed by two tandem sterile alpha motif (SAM) domains and a carboxyl phosphotyrosine binding (PTB) domain []. SAM domains of ANKS1 can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor []. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. The second SAM domain may decouple from the first SAM domain to facilitate translocation of AIDA-1 to the nucleus [].
Tissue-type plasminogen activator is a serine peptidase belonging to MEROPS peptidase family S1 (chymotrypsin family, clan PA(S)), subfamily S1A.The fibrinolytic system is the mechanism by which blood clots are dissolved via the plasmin-mediated degradation of fibrin into soluble end products. The system is activated by urokinase-type plasminogen activator (uPA; ) or by tissue-type plasminogen activator (tPA; ; this family), which are enzymes that convert the inactive proenzyme plasminogen to the active protease plasmin [].tPA is mainly involved in the activation of circulating plasminogen, while uPA activates cell-bound plasminogen after binding to a specific uPA receptor (uPAR).Following the signal sequence and propeptide regions, tPA typically contains a fibronectin type I (FN1) domain, an EGF-type domain, two kringle domains and a trypsin domain. However, there are members missing FN1 or EGF or one of the kringles.This entry also includes salivary plaminogen activators from the vampire bat (Desmodus rotundus).
This entry represents the PX domain found in Sorting nexin-5 (SNX5). The PX domain of SNX5 binds phosphatidylinositol-3-phosphate (PI3P) and PI(3,4)P2. SNX5 is localized to a subdomain of early endosome and is recruited to the plasma membrane following EGF stimulation and elevation of PI(3,4)P2 levels [].The Phox Homology (PX) domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds phosphoinositides (PIs) and targets the protein to PI-enriched membranes [, ]. SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway [, , ].
Fibulins are a family of ECM glycoproteins characterized by a fibulin-type C-terminal domain preceded by tandem calcium-binding epidermal growth factor (EGF)-like modules. They are involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. There are five fibulins, which can be classified into two subgroups. Fibulin-1 and -2 constitute one subgroup. These fibulins are larger than the others due to the presence of a higher number of EGF modules and an extra domain with three anaphylatoxin modules []. Members of the second subgroup, fibulin-3, -4, and -5, are similarly small in size and highly homologous to one another in modular structure. They consist of a modified cbEGF domain at the N terminus followed by five tandem cbEGF modules and the fibulin-type C-terminal region.This entry represents the fibulin-1 proteins, which are incorporated into fibronectin-containing matrix fibres and may play a role in cell adhesion and migration [].
Matrilin family consists of four non-collagenous extracellular matrix (ECM) proteins []. Matrilin-1 and matrilin-3 are expressed mainly in cartilage, while matrilin-2 and matrilin-4 are widely distributed in many connective tissues []. Typical matrilin has the similar domain structure with two von Willebrand factor A-like (VWA) domains interconnected by a variable number of epidermal growth factor-like (EGF) domains. The subunits form trimers or tetramers via a C-terminal α-helical coiled-coil domain [].Matrilin-2 (MATN2) is the largest and most complex matrilin. It is made up by two vWFA-like domains connected by ten EGF modules, and has a unique domain located between the second vWFA-like domain and the coiled-coil C-terminal domain []. MATN2 is a structural component of the ECM in many tissues, including the skin [, ]. It participates in peripheral nerve regeneration []and induces proinflammatory responses that could contribute to axonal damage in CNS inflammatory diseases []. It functions as a tumor suppressor in hepatocarcinogenesis [].
Fibulins are a family of ECM glycoproteins characterized by a fibulin-type C-terminal domain preceded by tandem calcium-binding epidermal growth factor (EGF)-like modules. They are involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. There are five fibulins, which can be classified into two subgroups. Fibulin-1 and -2 constitute one subgroup. These fibulins are larger than the others due to the presence of a higher number of EGF modules and an extra domain with three anaphylatoxin modules []. Members of the second subgroup, fibulin-3, -4, and -5, are similarly small in size and highly homologous to one another in modular structure. They consist of a modified cbEGF domain at the N terminus followed by five tandem cbEGF modules and the fibulin-type C-terminal region.Fibulin-5 is a critical molecule for elastic fibre assembly. It may also have a role in regulating protease activity by interacting with beta-1 integrin as an endogenous competitive ligand [].
PACSIN1 and PACSIN2 belong to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain []. They are cytoplasmic phosphoproteins that play a role in vesicle formation and transport [].PACSIN1 (also known as Syndapin-1) is upregulated upon differentiation into neuronal cells []. The SH3 domain of PACSIN1 mediates activation of neural WASP (N-WASP), which is required to regulate actin polymerisation and is essential for proper neuromorphogenesis and cellular motility []. Two phosphorylation sites within the F-BAR domain of PACSIN1 are used for membrane tubulation regulation []. PACSIN2 interacts with several proteins such as Rac1, dynamin, Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP), and synaptojanin via its C-terminal SH3 domain []. PACSIN2 negatively regulates the EGF (epidermal growth factor) receptor activation and signaling [, ]. It plays an important role in caveolae membrane sculpting []. This entry represents the SH3 domain of PACSINs 1 and 2.
PACSIN2 (protein kinase C and casein kinase substrate in neurons protein 2, also known as Syndapin-2) belongs to the PACSIN family that contains a N-terminal F-BAR (FCH-BAR) domain and a C-terminal SH3 domain []. They are cytoplasmic phosphoproteins that play a role in vesicle formation and transport []. PACSIN2 interacts with several proteins such as Rac1, dynamin, Neuronal Wiskott-Aldrich Syndrome Protein (N-WASP), and synaptojanin via its C-terminal Src homology 3 (SH3) domain []. PACSIN2 negatively regulates the EGF (epidermal growth factor) receptor activation and signaling [, ]. It plays an important role in caveolae membrane sculpting []. This entry represents the F-BAR domain of PACSIN2. F-BAR domains are dimerization modules that bind and bend membranes and are found in proteins involved in membrane dynamics and actin reorganization [].
Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates [, , , , ]. Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few []. Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target. This entry represents ZPR1-type zinc finger domains. An orthologous protein found once in each of the completed archaeal genomes corresponds to a zinc finger-containing domain repeated as the N-terminal and C-terminal halves of themouse protein ZPR1. ZPR1 is an experimentally proven zinc-binding protein that binds the tyrosine kinase domain of the epidermal growth factor receptor (EGFR); binding is inhibited by EGF stimulation and tyrosine phosphorylation, and activation by EGF is followed by some redistribution of ZPR1 to the nucleus. By analogy, other proteins with the ZPR1 zinc finger domain may be regulatory proteins that sense protein phosphorylation state and/or participate in signal transduction (see also ).Deficiencies in ZPR1 may contribute to neurodegenerative disorders. ZPR1 appears to be down-regulated in patients with spinal muscular atrophy (SMA), a disease characterised by degeneration of the alpha-motor neurons in the spinal cord that can arise from mutations affecting the expression of Survival Motor Neurons (SMN) []. ZPR1 interacts with complexes formed by SMN [], and may act as a modifier that effects the severity of SMA.
The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes, while the receptor returns to the cell surface []. The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing: The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation []. Similar domains have been found in other extracellular and membrane proteins []. The second conserved region contains two EGF repeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a β-propeller structure []. This region is critical for ligand release and recycling of the receptor [].The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.The fourth domain is the hydrophobic transmembrane region.The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins [].This entry represents the LDLR class A (cysteine-rich) repeat, which contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module []. In LDL receptors, the class A domains form the binding site for LDL and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands. The repeat consists of a β-hairpin structure followed by a series of beta turns. In the absence of calcium, LDL-A domains are unstructured; the bound calcium ion imparts structural integrity. Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor. Numerous familial hypercholesterolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.
The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes,while the receptor returns to the cell surface []. The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing: The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation []. Similar domains have been found in other extracellular and membrane proteins []. The second conserved region contains two EGF repeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a β-propeller structure []. This region is critical for ligand release and recycling of the receptor [].The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.The fourth domain is the hydrophobic transmembrane region.The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins [].This entry represents the LDLR classB (YWTD) repeat, the structure of which has been solved []. The six YWTD repeats together fold into a six-bladed β-propeller. Each blade of the propeller consists of four antiparallel β-strands; the innermost strand of each blade is labeled 1 and the outermost strand, 4. The sequence repeats are offset with respect to the blades of the propeller, such that any given 40-residue YWTD repeat spans strands 24 of one propeller blade and strand 1 of the subsequent blade. This offset ensures circularization of the propeller because the last strand of the final sequence repeat acts as an innermost strand 1 of the blade that harbors strands 24 from the first sequence repeat. The repeat is found in a variety of proteins that include, vitellogenin receptor from Drosophila melanogaster, low-density lipoprotein (LDL) receptor [], preproepidermal growth factor, and nidogen (entactin).
The netrin (NTR) module is an about 130-residue domain found in the C-terminal parts of netrins, complement proteins C3, C4, and C5, secreted frizzled-related proteins, and type I procollagen C-proteinase enhancer proteins (PCOLCEs), as well as in the N-terminal parts of tissue inhibitors of metalloproteinases (TIMPs). The proteins harboring the NTR domain fulfill diverse biological roles ranging from axon guidance, regulation of Wnt signalling, to the control of the activity of metalloproteinases. The NTR domain can be found associated to other domains such as CUB, WAP, Kazal, Kunitz, Ig-like, laminin N-terminal, laminin-type EGF or frizzled. The NTR domain is implicated in inhibition of zinc metalloproteinases of the metzincin family [, ].The NTR module is a basic domain containing six conserved cysteines, which are likely to form internal disulphide bonds, and several conserved blocks of hydrophobic residues (including an YLLLG-like motif). The NTR module consists of a β-barrel with two terminal α-helices packed side by side against the face of the β-barrel (see ) [].This entry includes most netrin modules, but excludes those found in TIMPs.
A sequence of about thirty to forty amino-acid residues long found in the sequence of epidermal growth factor (EGF) has been shown [, , , ]to be present, in a more or less conserved form, in a large number of other, mostly animal, proteins. EGF is a polypeptide of about 50 amino acids with three internal disulfide bridges. It first binds with high affinity to specific cell-surface receptors and then induces their dimerization, which is essential for activating the tyrosine kinase in the receptor cytoplasmic domain, initiating a signal transduction that results in DNA synthesis and cell proliferation.A common feature of all EGF-like domains is that they are found in the extracellular domain of membrane-bound proteins or in proteins known to besecreted (exception: prostaglandin G/H synthase). The EGF-like domain includes six cysteine residues which have been shown to be involved in disulfide bonds. The structure of several EGF-like domains has been solved. The fold consists of two-stranded β-sheet followed by a loop to a C-terminal shorttwo-stranded sheet.
Sorting nexins (SNXs) are a diverse group of cellular trafficking proteins that are unified by the presence of a phospholipid-binding motif, the PX domain. The ability of these proteins to bind specific phospholipids, as well as their propensity to form protein-protein complexes, points to a role for these proteins in membrane trafficking and protein sorting []. Members of this group also contain coiled-coil regions within their large C-terminal domains and a BAR domain, whose function has been defined as a dimerisation motif, as sensing and inducing membrane curvature, and/or likely to bind to small GTPases [].This entry includes SNX5, SNX6 and SNX32 (also known as SNX6B).SNX5 contains a BAR domain that is C teminus to the PX domain. SNX5 plays a role in macropinocytosis []and in the internalisation of EGFR after EGF stimulation [].SNX6 was found to interact with members of the transforming growth factor-beta family of receptor serine/threonine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation in vivoof oligomeric complexes. SNX6 is localized in the cytoplasm where it is thought to target proteins to the trans-Golgi network []. In addition, SNX6 was found to be translocated from the cytoplasm to nucleus by Pim-1, an oncogene product of serine/threonine kinase. This translocation is not affected by Pim-1-dependent phosphorylation, but the functional significance is unknown [].
Laminin is a large molecular weight glycoprotein present only in basementmembranes in almost every animal tissue. Each laminin is a heterotrimerassembled from alpha, beta and gamma chain subunits, secreted and incorporatedinto cell-associated extracellular matrices. The laminins can self-assemble,bind to other matrix macromolecules, and have unique and shared cellinteractions mediated by integrins, dystroglycan, and other receptors. Throughthese interactions, laminins critically contribute to cell differentiation,shape and movement, maintenance of tissue phenotypes,and promotion of tissuesurvival [, ].The different laminin chains share a 600-residue domain I/II whicholigomerises into a rod-like coiled-coil structure forming the long arm oflaminins. The N-terminal short arms consist of rod-like elements (domain IIIand V) formed by tandem arrays of laminin-type EGF modulesand several globular domains: domains IV and domain VI (lamininN-terminal). All alpha chains share a unique C-terminal Gdomain which consists of five laminin G modules []. Laminin IV domain is also found in the perlecan protein, an integral component ofbasement membranes, which serves also as an attachment substrate for cells,but it is not found in short laminin chains (alpha4 or beta3). The function ofthis domain is not yet known.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Some receptors share a common beta chain while having different alpha chains [, ]. A number of different beta chains, beta-1 to beta-8 are known in higher eukaryotes.This entry represents the family of integrin beta subunit proteins. It also includes integrin beta-like protein 1, whose function is unknown.
Fibulins are a family of ECM glycoproteins characterized by a fibulin-type C-terminal domain preceded by tandem calcium-binding epidermal growth factor (EGF)-like modules. They are involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. There are five fibulins, which can be classified into two subgroups. Fibulin-1 and -2 constitute one subgroup. These fibulins are larger than the others due to the presence of a higher number of EGF modules and an extra domain with three anaphylatoxin modules []. Members of the second subgroup, fibulin-3, -4, and -5, are similarly small in size and highly homologous to one another in modular structure. They consist of a modified cbEGF domain at the N terminus followed by five tandem cbEGF modules and the fibulin-type C-terminal region.This entry represents EGF-containing fibulin-like extracellular matrix protein 2 (Efemp2), also known as fibulin-4. Efemp2 binds to tropoelastin and may play an important role in the assembly of elastic fibres during development []. Defects in Efemp2 cause autosomal recessive cutis laxa, an heterogeneous group of connective tissue disorders characterised by cutaneous abnormalities and variable systemic manifestations such as loose skin. In addition to skin, internal organs enriched in elastic fibres, such as the lung and the arteries, are alsoaffected [, , ].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represents the cytoplasmic domain of integrin beta subunits [].
Factor VII (F7) initiates the extrinsic pathway of blood coagulation. It contains an N-terminal Gla domain followed by two epidermal growth factor-like domains (EGF1 and EGF2) and a C-terminal trypsin-like serine protease domain. It can be transformed into active forms (FVIIa) by proteolytic cleavage of the activation peptide located in the connecting region between the EGF2 and the protease domain; this results in the formation of a two-chain FVIIa molecule and a heavy chain held together by a single disulfide bond []. Its first EGF domain (EGF1) binds a calcium ion at its N terminus [].At an injury site, initiation of coagulation begins by exposure of blood to tissue factor (TF) in the extravascular space and formation of the Ca2+-dependent complex between TF and plasma FVIIa. The Ca2+/FVIIa/TF complex formed on the cell surfaces then activates both FX and FIX leading to thrombin generation and fibrin formation []. Mutations in the F7 gene cause Factor VII deficiency (FA7D), the most frequent among rare congenital bleeding disorders [].
The Notch domain is also called the 'DSL' domain or the Lin-12/Notch repeat (LNR). The LNR region is present only in Notch related proteins C-terminal to EGF repeats. The lin-12/Notch proteins act as transmembrane receptors for intercellular signals that specify cell fates during animal development. In response to a ligand, proteolytic cleavages release the intracellular domain of Notch, which then gains access to the nucleus and acts as a transcriptional co-activator []. The LNR region is supposed to negatively regulate the Lin-12/Notch proteins activity. It is a triplication of an around 35-40 amino acids module present on the extracellular part of the protein [, ]. Each module contains six cysteine residues engaged in three disulphide bonds and three conserved aspartate and asparagine residues []. The biochemical characterisation of a recombinantly expressed LIN-12.1 module from the human Notch1 receptor indicate that the disulphide bonds are formed between the firstand fifth, second and fourth, and third and sixth cysteines. The formation of this particular disulphide isomer is favored by the presence of Ca2+,which is also required to maintain the structural integrity of the rLIN-12.1 module. The conserved aspartate and asparagine residues are likely to be important for Ca2+binding, and thereby contribute to the native fold.
The SH2-containing Shc adapter proteins are targets of activated tyrosine kinases and are implicated in the transmission of activation signals to the Ras/mitogen-activated protein kinase (MAPK) pathway []. Three Shc genes were originally identified in mammals that encode proteins characterised by an amino-terminal phosphotyrosine binding (PTB) domain and a carboxy-terminal Src homology 2 domain. Shc1 (ShcA) is ubiquitously expressed, whereas expression of Shc2 (ShcB) and Shc3 (ShcC) appears to be limited to neuronal cells [].SHC is composed of an N-terminal domain that interacts with proteins containing phosphorylated tyrosines, a (glycine/proline)-rich collagen-homology domain that contains the phosphorylated binding site, and a C-terminal SH2 domain. SH2 has been shown to interact with the tyrosine-phosphorylated receptors of EGF and PDGF and with the tyrosine-phosphorylated C chain of the T-cell receptor, providing one of the mechanisms of T-cell-mediated Ras activation []. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites [, , ].
Carboxypeptidase M (CPM; MEROPS identifier M14.006; ) is an extracellular glycoprotein, bound to cell membranes via a glycosyl-phosphatidylinositol on the C terminus of the protein []. It specifically removes C-terminal basic residues (Arg or Lys) from peptides and proteins [, ]. The highest levels of CPM have been found in human lung and placenta, but significant amounts are present in kidney, blood vessels, intestine, brain, and peripheral nerves. CPM has also been found in soluble form in various body fluids, including amniotic fluid, seminal plasma and urine. Due to its wide distribution in a variety of tissues, it is believed that it plays an important role in the control of peptide hormones and growth factor activity on the cell surface and in the membrane-localized degradation of extracellular proteins. For example, it hydrolyses the C-terminal arginine of epidermal growth factor (EGF) resulting in des-Arg-EGF which binds to the EGF receptor (EGFR) with an equal or greater affinity than native EGF. CPM is a required processing enzyme that generates specific agonists for the B1 receptor [, ].This entry represents the carboxypeptidase (N-terminal) domain of carboxypeptidase M.
Avidin []is a minor constituent of egg white in several groups of oviparous vertebrates. Avidin, which was discovered in the 1920's, takes its name from the avidity with which it binds biotin. These two molecules bind so strongly that is extremely difficult to separate them. Streptavidin is a protein produced by Streptomyces avidinii which also binds biotin and whose sequence is evolutionary related to that of avidin.Avidin and streptavidin both form homotetrameric complexes of noncovalently associated chains. Each chain forms a very strong and specific non-covalent complex with one molecule of biotin. The three-dimensional structures of both streptavidin [, ]and avidin []have been determined and revealed them to share a common fold: an eight stranded anti-parallel β-barrel with a repeated +1 topology enclosing an internal ligand binding site.Fibropellins I and III []are proteins that form the apical lamina of the sea urchin embryo, a component of the extracellular matrix. These two proteins have a modular structure composed of a CUB domain (see), followed by a variable number of EGF repeats and a C-terminal avidin-like domain.
This entry represents the CFC domain found in the membrane protein Cripto (or teratocarcinoma-derived growth factor), a protein over expressed in many tumours [, ]and structurally similar to the C-terminal extracellular portions of Jagged 1 and Jagged 2 []. CFC is approx 40-residues long, compacted by three internal disulphide bridges, and binds Alk4 via a hydrophobic patch. CFC is structurally homologous to the VWFC-like domain []. The protein Cripto is the founding member of the extra-cellular EGF-CFC growth factors, which are composed of two adjacent cysteine-rich domains: the EGF-like and the CFC domains. Members of the EGF-CFC family play key roles in embryonic development and are also implicated in tumourigenesis []. The Cripto protein could play a role in the determination of the epiblastic cells that subsequently give rise to the mesoderm. Although both the EGF and CFC domains are involved in the tumourigenic activity of Crispto proteins, the CFC domain appears to play a crucial role, as it is through the CFC domain that Crispto interferes with the onco-suppressive activity of Activins, either by blocking the Activin receptor ALK4 or by antagonising proteins of the TGF-beta family []. The Cryptic protein is involved in the correct establishment of the left-right axis. May play a role in mesoderm and/or neural patterning during gastrulation.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This superfamily represent the C-terminal domain of integrin alpha (which can be further subdivided in the thight, calf-1 and calf-2 domains) and the central region of integrin beta known as the hybrid domain [].
Avidin []is a minor constituent of egg white in several groups of oviparous vertebrates. Avidin, which was discovered in the 1920's, takes its name from the avidity with which it binds biotin. These two molecules bind so strongly that is extremely difficult to separate them. Streptavidin is a protein produced by Streptomyces avidinii which also binds biotin and whose sequence is evolutionary related to that of avidin.Avidin and streptavidin both form homotetrameric complexes of noncovalently associated chains. Each chain forms a very strong and specific non-covalent complex with one molecule of biotin. The three-dimensional structures of both streptavidin [, ]and avidin []have been determined and revealed them to share a common fold: an eight stranded anti-parallel β-barrel with a repeated +1 topology enclosing an internal ligand binding site.Fibropellins I and III []are proteins that form the apical lamina of the sea urchin embryo, a component of the extracellular matrix. These two proteins have a modular structure composed of a CUB domain (see), followed by a variable number of EGF repeats and a C-terminal avidin-like domain.
Avidin []is a minor constituent of egg white in several groups of oviparous vertebrates. Avidin, which was discovered in the 1920's, takes its name from the avidity with which it binds biotin. These two molecules bind so strongly that is extremely difficult to separate them. Streptavidin is a protein produced by Streptomyces avidinii which also binds biotin and whose sequence is evolutionary related to that of avidin.Avidin and streptavidin both form homotetrameric complexes of noncovalently associated chains. Each chain forms a very strong and specific non-covalent complex with one molecule of biotin. The three-dimensional structures of both streptavidin [, ]and avidin []have been determined and revealed them to share a common fold: an eight stranded anti-parallel β-barrel with a repeated +1 topology enclosing an internal ligand binding site.Fibropellins I and III []are proteins that form the apical lamina of the sea urchin embryo, a component of the extracellular matrix. These two proteins have a modular structure composed of a CUB domain (see), followed by a variable number of EGF repeats and a C-terminal avidin-like domain.
Avidin []is a minor constituent of egg white in several groups of oviparous vertebrates. Avidin, which was discovered in the 1920's, takes its name from the avidity with which it binds biotin. These two molecules bind so strongly that is extremely difficult to separate them. Streptavidin is a protein produced by Streptomyces avidinii which also binds biotin and whose sequence is evolutionary related to that of avidin. Avidin and streptavidin both form homotetrameric complexes of noncovalently associated chains. Each chain forms a very strong and specific non-covalent complex with one molecule of biotin.The three-dimensional structures of both streptavidin [, ]and avidin []have been determined and revealed them to share a common fold: an eightstranded anti-parallel β-barrel with a repeated +1 topology enclosing aninternal ligand binding site.Fibropellins I and III []are proteins that form the apical lamina of the seaurchin embryo, a component of the extracellular matrix. These two proteinshave a modular structure composed of a CUB domain (see), followedby a variable number of EGF repeats and a C-terminal avidin-like domain. This entry represents this avidin-like domain.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrin beta-5 associates with alpha-V. It is a key integrin involved in angiogenesis, vasculogenesis, hematopoiesis and bone formation [].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrin Beta-6 associates with Alpha-V to form the receptor for the TGFB1 latency-associated peptide (LAP) []. Cells expressing this integrin combination induce spatially restricted activation of TGFB1, while mice lacking the integrin display exaggerated inflammation and are protected from pulmonary fibrosis.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.The Integrin beta-8 subunit is a 95kDa glycosylated polypeptide that is typical of other beta chain integrins. It associates with the Alpha-V chain and this heterodimer is found in mature synapses of mouse and rat brains.
Laminin is a large molecular weight glycoprotein present only in basement membranes in almost every animal tissue. Each laminin is a heterotrimer assembled from alpha, beta and gamma chain subunits, secreted and incorporated into cell-associated extracellular matrices. The laminins can self-assemble, bind to other matrix macromolecules, and have unique and shared cell interactions mediated by integrins, dystroglycan, and other receptors. Through these interactions, laminins critically contribute to cell differentiation, shape and movement, maintenance of tissue phenotypes, and promotion of tissue survival [, ]. The different laminin chains share a 600-residue domain I/II which oligomerizes into a rod-like coiled-coil structure forming the long arm of laminins. The N-terminal short arms consist of rod-like elements (domain III and V) formed by tandem arrays of laminin-type EGF modules and several globular domains: domains IV and domain VI (laminin N-terminal). All alpha chains share a unique C-terminal G domain which consists of five laminin G modules []. Laminin IV domain is also found in the perlecan protein, an integral component of basement membranes, which also serves as an attachment substrate for cells, but it is not found in short laminin chains (alpha4 or beta3). The function of this domain is not yet known. The domain IV of laminin beta chains displays no sequence homology to other laminin IV domains. This entry represents this atypical domain IV.
Fibulins are a family of ECM glycoproteins characterized by a fibulin-type C-terminal domain preceded by tandem calcium-binding epidermal growth factor (EGF)-like modules. They are involved in protein-protein interaction with the components of basement membrane and extracellular matrix proteins. There are five fibulins, which can be classified into two subgroups. Fibulin-1 and -2 constitute one subgroup. These fibulins are larger than the others due to the presence of a higher number of EGF modules and an extra domain with three anaphylatoxin modules []. Members of the second subgroup, fibulin-3, -4, and -5, are similarly small in size and highly homologous to one another in modular structure. They consist of a modified cbEGF domain at the N terminus followed by five tandem cbEGF modules and the fibulin-type C-terminal region.Fibulin-2 is the largest of all the fibulins, because it possesses an additional N-terminal domain not found in other fibulins. Fibulin-2 and fibulin-1 overlap in their binding patterns, which ligands that include fibronectin, proteoglycans, tropoelastin, and various elastic fibre and basement membrane proteins. Only a couple of ligands are specific for fibulin-1 (fibrinogen and laminin-1) and for fibulin-2 (fibrillin-1 and perlecan) []. Expression of the fibulin-2 initiates later than fibulin-1 during embryonic development and is distributed in a more restricted manner.
The Notch domain is also called the 'DSL' domain or the Lin-12/Notch repeat (LNR). The LNR region is present only in Notch related proteins C-terminal to EGF repeats. The lin-12/Notch proteins act as transmembrane receptors for intercellular signals that specify cell fates during animal development. In response to a ligand, proteolytic cleavages release the intracellular domain of Notch, which then gains access to the nucleus and acts as a transcriptional co-activator []. The LNR region is supposed to negatively regulate the Lin-12/Notch proteins activity. It is a triplication of an around 35-40 amino acids module present on the extracellular part of the protein [, ]. Each module contains six cysteine residues engaged in three disulphide bonds and three conserved aspartate and asparagine residues []. The biochemical characterisation of a recombinantly expressed LIN-12.1 module from the human Notch1 receptor indicate that the disulphide bonds are formed between the firstand fifth, second and fourth, and third and sixth cysteines. The formation of this particular disulphide isomer is favored by the presence of Ca2+, which is also required to maintain the structural integrity of the rLIN-12.1 module. The conserved aspartate and asparagine residues are likely to be important for Ca2+binding, and thereby contribute to the native fold.
Animal lectins display a wide variety of architectures.They are classified according to the carbohydrate-recognitiondomain (CRD) of which there are two main types, S-type and C-type.C-type lectins display a wide range of specificities.They require Ca2+for their activityThey are found predominantly but not exclusively in vertebrates.They can be classified into a number of subgroups based on their function and structure:Endocytic lectins - Membrane-bound receptors that mediate endocytosis of glycoproteinsCollectins -Represented by the soluble mannose-binding proteins of mammalian serum and liver Selectins - Membrane-bound proteins involved in inflammation. There are three main divisions, CD62E, CD62 L and CD62P [].CD62E (also called E-selectin, ELAM-1 or LECAM-2), CD62L (also called L-selectin, LAM-1, LECAM-1, Leu-8, MEL-14 or TQ-1) and CD62P (also called P-selectin, granule membrane protein-140, GMP-140 or platelet activation dependent granule-external membrane protein, PADGEM) belong to this group.CD62E mediates leukocyte rolling on activated endothelium at inflammatory sites and may also support tumor cell adhesion during hematogenous metastasis, and play a role in angiogenesis. CD62L mediates lymphocyte homing to high endothelial venules of peripheral lymphoid tissue and leukocyte rolling on activated endothelium at inflammatory sites. Interaction of CD62P with PSGL-1 mediates tethering and rolling of leukocytes on the surface of activated endothelial cells, the first step in leukocyte extravasation and migration towards inflammations. CD62P mediates rolling of platelets on endothelial cells and CD62P-mediated interactions are also involved in platelet-mediated delivery of lymphocytes to high endothelial venules.Members of the selectin superfamily have the same domain structure: an N-terminal lectin domain followed by an EGF repeat; a variable number (between 2 and 9) of complement regulatory elements; a single trans-membrane region; and a short cytoplasmic anchor. Some studies have found distinct carbohydrate structures on leukocytes that are adhered to byselectins, suggesting that selectins are involved in the selective trafficking of blood-borne components of the immune system.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This group represents a group of known and predicted receptor-type tyrosine-protein kinases, including the EGF and ERB receptors, and the melanoma-inducing oncogene product XmrK.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.The beta 4 subunit differs from other beta subunits in three ways: 1) the cytoplasmic domain is larger; 2) it lacks some of the conserved cysteines in the extracellular domain; and 3) it has a unique domain organisation.Integrin alpha-6/beta-4 is a receptor for laminin. It plays a critical structural role in the hemidesmosome of epithelial cells []. Integrin beta-4 is required for the regulation of keratinocyte polarity and motility [].For additional information please see [, , , , , , , ].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represents the tail domain of the integrin beta subunit. It forms a four-stranded β-sheet that contains parallel and antiparallel strands and faces an alpha helix foundat the N terminus of this domain []. Interactions between the α-helix and the β-sheet are mostly hydrophobic and involve a disulphide bond. The rear of the beta sheet is covered with a long A-B loop.
The CUB domain (for complement C1r/C1s, Uegf, Bmp1) is a structural motif of approximately 110 residues found almost exclusively in extracellular and plasma membrane-associated proteins, many of which are developmentally regulated [, ]. These proteins are involved in a diverse range of functions, including complement activation, developmental patterning, tissue repair, axon guidance and angiogenesis, cell signalling, fertilisation, haemostasis, inflammation, neurotransmission, receptor-mediated endocytosis, and tumour suppression []. Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin). Proteins containing a CUB domain include:Mammalian complement subcomponents C1s/C1r, which form the calcium-dependent complex C1, the first component of the classical pathway of the complement system.Cricetidae sp. (Hamster) serine protease Casp, which degrades type I and IV collagen and fibronectin in the presence of calcium.Mammalian complement-activating component of Ra-reactive factor (RARF), a protease that cleaves the C4 component of complement.Vertebrate enteropeptidase (), a type II membrane protein of the intestinal brush border, which activates trypsinogen.Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and expresses metalloendopeptidase activity.Sea urchin blastula proteins BP10 and SpAN.Caenorhabditis elegans hypothetical proteins F42A10.8 and R151.5.Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that functions during the formation of certain neuronal circuits.Fibropellins I and III from Strongylocentrotus purpuratus (Purple sea urchin).Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein.Mammalian spermadhesins.Xenopus laevis embryonic protein UVS.2, which is expressed during dorsoanterior development.Several of the above proteins consist of a catalytic domain together with several CUB domains interspersed by calcium-binding EGF domains. Some CUB domains appear to be involved in oligomerisation and/or recognition of substrates and binding partners. For example, in the complement proteases, the CUB domains mediate dimerisation and binding to collagen-like regions of target proteins (e.g. C1q for C1r/C1s). The structure of CUB domains consists of a β-sandwich with a jelly-roll fold. Almost all CUB domains contain four conserved cysteines that probably form two disulphide bridges (C1-C2, C3-C4). The CUB1 domains of C1s and Map19 have calcium-binding sites [].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represents the tail domain of the integrin beta subunit. It forms a four-stranded β-sheet that contains parallel and antiparallel strands and faces an alpha helix found at the N terminus of this domain []. Interactions between the α-helix and the β-sheet are mostly hydrophobic and involve a disulphide bond. The rear of the beta sheet is covered with a long A-B loop.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has twoshort cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.This entry represent integrin beta-1. Beta-1 integrin associates with alpha subunits to form receptor complexes that bind a variety of ligands. Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen. Integrins alpha-2/beta-1, alpha-3/beta-1, alpha-4/beta-1, alpha-5/beta-1, alpha-8/beta-1, alpha-10/beta-1, alpha-11/beta-1 and alpha-V/beta-1 are receptors for fibronectin. Integrin alpha-5/beta-1 is a receptor for fibrinogen. Integrin alpha-1/beta-1, alpha-2/beta-1, alpha-6/beta-1 and alpha-7/beta-1 are receptors for lamimin. Alpha7beta1 integrin regulates cell adhesion and laminin matrix deposition []. Integrin alpha-4/beta-1 is a receptor for VCAM1. Integrin alpha-9/beta-1 is a receptor for VCAM1, cytotactin and osteopontin. Integrin alpha-3/beta-1 is a receptor for epiligrin, thrombospondin and CSPG4 and has a role in endothelial cell motility and angiogenesis [].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrin Beta-7 was originally identified in leukocytes. It is 32 to 46% homologous to integrins 1 through 6, which are also found in leukocytes []. Like the other integrins, integrin beta-7 is involved in cell adhesion. With Integrin Alpha-4, Beta-7 forms a receptor that is essential for intestinal homing of effector/memory T cells [].
The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes, while the receptor returns to the cell surface []. The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing: The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation []. Similar domains have been found in other extracellular and membrane proteins []. The second conserved region contains two EGFrepeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a β-propeller structure []. This region is critical for ligand release and recycling of the receptor [].The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.The fourth domain is the hydrophobic transmembrane region.The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins [].This entry represents the LDLR class A (cysteine-rich) repeat, which contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module []. In LDL receptors, the class A domains form the binding site for LDL and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands. The repeat consists of a β-hairpin structure followed by a series of beta turns. In the absence of calcium, LDL-A domains are unstructured; the bound calcium ion imparts structural integrity. Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor. Numerous familial hypercholesterolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Some alpha subunits are cleaved post-translationally to produce a heavy and a light chain linked by a disulphidebond [, ]. Integrin alpha chains share a conserved sequence which is found atthe beginning of the cytoplasmic domain, just after the end of thetransmembrane region. Within the N-terminal domain of alpha subunits, seven sequence repeats, eachof approximately 60 amino acids, have been found []. It has been predicted that these repeats assume the β-propeller fold. The domains contain seven four-stranded β-sheets arranged in a torus around a pseudosymmetry axis[]. Integrin ligands and a putative Mg2+ion are predicted to bind to theupper face of the propeller, in a manner analogous to the way in which thetrimeric G-protein beta subunit (G beta) (which also has a β-propellerfold) binds the G protein alpha subunit [].Integrin cytoplasmic domains are normally less than 50 amino acids in length, with the beta-subunit sequencesexhibiting greater homology to each other than the alpha-subunit sequences []. This is consistent withcurrent evidence that the beta subunit is the principal site for binding of cytoskeletal and signallingmolecules, whereas the alpha subunit has a regulatory role. The first ten residues of thealpha-subunit cytoplasmic domain appear to form an alpha helix that is terminated by a proline residue. Theremainder of the domain is highly acidic in nature and this loops back to contact themembrane-proximal lysine anchor residue.
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrin Beta-2 is also referred to as ITGB2 and is known to interact with three different alpha integrin chains: ITGAL, ITGAM and ITGAX. These three integrin heterodimers are associated with leukocyte adhesion deficiency (LAD), which is characterised by recurrent bacterial infections. LFA-1 (ITGB2/ITGAL) is one of the most well studied of these integrins. Engagement of LFA-1 results in increased AP-1 dependent gene expression, which is mediated by the nuclear translocation of JAB1 []. The ligand for LFA-1 is JAM-1, a member of the endothelial immunoglobulin superfamily. JAM-1 contributes to LFA-1 dependent transendothelial migration of leukocytes and LFA-1 mediated arrest of T cells []. Studies of marginal zone (MZ) B cells also showed that LFA-1, together with alpha4beta1, is required for localisation of those cells in the splenic MZ and that these integrins are necessary for lymphoid tissue compartmentalization [].
The CUB domain (for complement C1r/C1s, Uegf, Bmp1) is a structural motif of approximately 110 residues found almost exclusively in extracellular and plasma membrane-associated proteins, many of which are developmentally regulated [, ]. These proteins are involved in a diverse range of functions, including complement activation, developmental patterning, tissue repair, axon guidance and angiogenesis, cell signalling, fertilisation, haemostasis, inflammation, neurotransmission, receptor-mediated endocytosis, and tumour suppression []. Many CUB-containing proteins are peptidases belonging to MEROPS peptidase families M12A (astacin) and S1A (chymotrypsin). Proteins containing a CUB domain include:Mammalian complement subcomponents C1s/C1r, which form the calcium-dependent complex C1, the first component of the classical pathway of the complement system.Cricetidae sp. (Hamster) serine protease Casp, which degrades type I and IVcollagen and fibronectin in the presence of calcium.Mammalian complement-activating component of Ra-reactive factor (RARF), a protease that cleaves the C4 component of complement.Vertebrate enteropeptidase (), a type II membrane protein of the intestinal brush border, which activates trypsinogen.Vertebrate bone morphogenic protein 1 (BMP-1), a protein which induces cartilage and bone formation and expresses metalloendopeptidase activity.Sea urchin blastula proteins BP10 and SpAN.Caenorhabditis elegans hypothetical proteins F42A10.8 and R151.5.Neuropilin (A5 antigen), a calcium-independent cell adhesion molecule that functions during the formation of certain neuronal circuits.Fibropellins I and III from Strongylocentrotus purpuratus (Purple sea urchin).Mammalian hyaluronate-binding protein TSG-6 (or PS4), a serum and growth factor induced protein.Mammalian spermadhesins.Xenopus laevis embryonic protein UVS.2, which is expressed during dorsoanterior development.Several of the above proteins consist of a catalytic domain together with several CUB domains interspersed by calcium-binding EGF domains. Some CUB domains appear to be involved in oligomerisation and/or recognition of substrates and binding partners. For example, in the complement proteases, the CUB domains mediate dimerisation and binding to collagen-like regions of target proteins (e.g. C1q for C1r/C1s). The structure of CUB domains consists of a β-sandwich with a jelly-roll fold. Almost all CUB domains contain four conserved cysteines that probably form two disulphide bridges (C1-C2, C3-C4). The CUB1 domains of C1s and Map19 have calcium-binding sites [].Structurally, the spermadhesins consist of a CUB domain [].
Integrins are the major metazoan receptors for cell adhesion to extracellular matrix proteins and, in vertebrates, also play important roles in certain cell-cell adhesions, make transmembrane connections to the cytoskeleton and activate many intracellular signalling pathways [, ]. An integrin receptor is a heterodimer composed of alpha and beta subunits. Each subunit crosses the membrane once, with most of the polypeptide residing in the extracellular space, and has two short cytoplasmic domains. Some members of this family have EGF repeats at the C terminus and also have a vWA domain inserted within the integrin domain at the N terminus.Most integrins recognise relatively short peptide motifs, and in general require an acidic amino acid to be present. Ligand specificity depends upon both the alpha and beta subunits []. There are at least 18 types of alpha and 8 types of beta subunits recognised in humans []. Each alpha subunit tends to associate only with one type of beta subunit, but there are exceptions to this rule []. Each association of alpha and beta subunits has its own binding specificity and signalling properties. Many integrins require activation on the cell surface before they can bind ligands. Integrins frequently intercommunicate, and binding at one integrin receptor activate or inhibit another.Integrins are important therapeutic targets in conditions such as atherosclerosis, thrombosis, cancer and asthma [].At the N terminus of the beta subunit is a cysteine-containing domain reminiscent of that found in presenillins and semaphorins, which has hence been termed the PSI domain. C-terminal to the PSI domain is an A-domain, which has been predicted to adopt a Rossmann fold similar to that of the alpha subunit, but with additional loops between the second and third beta strands []. The murine gene Pactolus shares significant similarity with the beta subunit [], but lacks either one or both of the inserted loops. The C-terminal portion of the beta subunit extracellular domain contains an internally disulphide-bonded cysteine-rich region, while the intracellular tail contains putative sites of interaction with a variety of intracellular signalling and cytoskeletal proteins, such as focal adhesion kinase and alpha-actinin respectively []. Integrin cytoplasmic domains are normally less than 50 amino acids in length, with the beta-subunit sequences exhibiting greater homology to each other than the alpha-subunit sequences. This is consistent with current evidence that the beta subunit is the principal site for binding of cytoskeletal and signalling molecules, whereas the alpha subunit has a regulatory role. The first 20 amino acids of the beta-subunit cytoplasmic domain are also alpha helical, but the final 25 residues are disordered and, apart from a turn that follows a conserved NPxY motif, appear to lack defined structure, suggesting that this is adopted on effector binding. The two membrane-proximal helices mediate the link between the subunits via a series of hydrophobic and electrostatic contacts.This domain corresponds to the integrin beta VWA domain.
Human epidermal growth factor (EGF)-like module containing mucin-like hormone receptor 1 (EMR1) is a surface receptor of unknown function that belongs to the EGF-seven-transmembrane (EGF-TM7) family of G-protein coupled receptors []. Human EMR1 has been reported to be expressed exclusively on eosinophils []. It is the the human homologue of F4/80, a monoclonal antibody that recognises a Mus musculus (Mouse) macrophage-restricted cell surface glycoprotein that has been extensively used to characterise macrophage populations in a wide range of immunological studies []. Little is known about its possible role in macrophage differentiation and function. The sequence of the F4/80 protein is similar to two protein superfamilies: the N-terminal region contains seven epidermal growth factor (EGF)-like domains, while the C-terminal region contains seven hydrophobic regions whose signature is consistent with membership of the secretin-like superfamily of GPCRs. The EGF and GPCR domains are separated from each other by a serine/threonine-rich domain, a feature reminiscent of mucin-like, single-span, integral membrane glycoproteins with adhesive properties [].This family also comprises EMR3, a marker for mature granulocytes [], and EMR4 [, ].G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products.
G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups []. The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence []. The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) [, , , , ]. GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice []. Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs [].The secretin-like GPCRs include secretin [], calcitonin [], parathyroid hormone/parathyroid hormone-related peptides []and vasoactive intestinal peptide [], all of which activate adenylyl cyclase and the phosphatidyl-inositol-calcium pathway. These receptors contain seven transmembrane regions, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins (however there is no significant sequence identity between these families, the secretin-like receptors thus bear their own unique '7TM' signature). Their N-terminal is probably located on the extracellular side of the membrane and potentially glycosylated. This N-terminal region contains a long conserved region which allows the binding of large peptidic ligand such as glucagon, secretin, VIP and PACAP; this region contains five conserved cysteines residues which could be involved in disulphide bond. The C-terminal region of these receptor is probably cytoplasmic. Every receptor gene in this family is encoded on multiple exons, and several of these genes are alternatively spliced to yield functionally distinct products. The Adhesion G Protein-Coupled Receptors (aGPCRs) constitute an evolutionary ancient membrane protein family. The receptors contain a 7-TM domain with phylogeny suggesting ancestry to the Family B/2 (secretin receptor family, Class B/2) G-Protein-Coupled Receptors. aGPCRs are distinguished by their large amino-terminal regions that typically contain multiple modular motifs such as EGF (Epidermal Growth Factor-like), cadherin and immunoglobulin domains as well as novel lineage-specific structures. A defining feature of aGPCRs is the GPCR Autoproteoolysis-Inducing (GAIN) domain linking the N-terminal structure to the 7-TM region. Most aGPCRs undergo autocatalytic cleavage here, at the GPCR proteolysis site (GPS) into N-terminal and C-terminal fragments [].Adhesion G protein-coupled receptor E2 (ADGRE2) protein is a member of the EGF-7TM subclass of aGPCRs and has an N-terminal extracellular region that consists of 5 tandem EGF-like adhesion domains, an internal mucin-like stalk domain containing a short G-protein proteolytic site and a C-terminal seven-pass transmembrane domain. ADGRE2 undergoes autocatalytic cleavage within its G-protein proteolytic site motif. It is expressed predominantly in myeloid leukocytes but also on the surface of lung mast cells and the HMC1 human mast-cell line. The endogenous ligand is dermatan sulfate. The most closely related paralogue of ADGRE2 is ADGRE5 (also called CD97). Ligand binding of ADGRE5 mediates cell-cell adhesion of leukocytes and mediates an essential role in leukocyte migration [].
