The calcium sensing receptor (CAS) from Arabidopsis is a thylakoid-localised phosphoprotein that possesses a single transmembrane domain that splits the protein into two halves: the N-terminal domain which binds Ca2 with low affinity and high capacity, and the C-terminal domain that contains a non-catalytic rhodanese homology domain and phosphorylation sites []. It modulates cytoplasmic Ca2 levels and it is required for proper stomatal regulation in response to elevated levels of external Ca2 []and it is also involved in de-etiolation []. This protein also plays a role in the STN7/STN8/TAP38 network of phosphorylation-mediated photoacclimation processes in Arabidopsis [].
The function of C2 calcium-dependent domain-containing protein 4C/4D is not known. The C2 domain is a Ca2 -dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking.
This entry represents a group of plant calcium-binding proteins, including KRP1/PBP1/KIC from Arabidopsis. KIC interacts with kinesin-like calmodulin binding protein (KCBP) and modulates its activity in response to changes in cytosolic Ca2 and regulates trichome morphogenesis [].
Na/Ca2 exchangers (NCX) are membrane transporters that play an essential role in maintaining the homeostasis of cytosolic Ca2 for cell signalling. Ca2 is moved into or out of the cytosol depending on Na concentration. NCXhas a symmetrical structure containing ten transmembrane helices, divided in two halves with a similar structure but opposite orientation. Based on its symmetry, NCX is able to catalyse bidirectional ion-exchange reactions. Four ion-binding sites cluster at the centre of the protein: one specific for Ca2 and three that likely bind Na. Two passageways allow for Na and Ca2 access to the central ion-binding sites from the extracellular side [, ].This superfamily entry represents the large central ion-binding region made up of 8 transmembrane helices, also known as the intracellular regulatory domain.
EF-hand calcium-binding domain-containing protein 9 (EFCAB9) is a pH-dependent Ca2 sensor modulating the channel activity and the domain organization of CatSper, a sperm-specific, pH-sensitive calcium channel essential for hyperactivated motility and male fertility [].
This family of membrane proteins are conserved from plants to humans, including CAND2 and CAND8 from Arabidopsis. CAND2 and CAND8 are predicted G-protein coupled receptors []. CAND2 plays a role in plants and microbes interactions []and acts as a phytomelatonin receptor that regulates stomatal closure through the Galpha subunit-mediated H2O2 production and Ca2 flux dynamics [].
Protein piccolo, also known as aczonin, is a neuron-specific presynaptic active zone scaffolding protein that mainly interacts with a detergent-resistant cytoskeletal-like subcellular fraction and is involved in the organization of the interplay between neurotransmitter vesicles, the cytoskeleton, and the plasma membrane at synaptic active zones []. It binds profilin, an actin-binding protein implicated in actin cytoskeletal dynamics []. It also functions as a presynaptic low-affinity Ca2 sensor and has been implicated in Ca2 regulation of neurotransmitter release []. Piccolo is a multi-domain protein containing two N-terminal FYVE zinc fingers, a polyproline tract, and a PDZ domain and two C-terminal C2 domains. This entry represents the first FYVE domain, which resembles a FYVE-related domain that is structurally similar to the canonical FYVE domains but lacks the three signature sequences: an N-terminal WxxD motif (x for any residue), the central basic R(R/K)HHCRxCG patch, and a C-terminal RVC motif.
The inositol 1,4,5-trisphosphate (IP3)3 receptors (IP3R) are tetrameric intracellular Ca2 release channels on the endoplasmic membrane that are activated by the ligand IP3 []. The mammalian IP3R family consists of three isoforms (IP3R1, IP3R2, and IP3R3). They form homotetrameric or heterotetrameric channels []. They contain three functional domains: an N-terminal IP3-binding domain, a channel-forming domain localized to the C terminus, and a regulatory/coupling domain connecting these two domains [].
STKs (serine/threonine kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. MLCK2 (or MYLK2) phosphorylates myosin regulatory light chain and controls the contraction of skeletal muscles []. It is a key regulator of cardiac contraction []. MLCK2 contains a single kinase domain near the C terminus followed by a regulatory segment containing an autoinhibitory Ca2 /calmodulin binding site.
This family of proteins is found in eukaryotes. There is a single completely conserved residue D that may be functionally important. The family includes CFAP276 and homologues. Bovin CFAP276 has been identified as a microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating []. Members of this family have been suggested to be involved in intracellular Ca2 homeostasis [].
A-kinase anchor protein 5 (AKAP5), also known as AKAP79, is a PKA anchoring protein that binds to adenylyl cyclase type 8 (AC8) and to regulate its responsiveness to store-operated Ca(2) entry (SOCE) []. The AKAP79 and AC8 interaction may occur in lipid raft domains of the plasma membrane, with palmitoylation of AKAP79 plays an important role in targeting the AKAP to the cholesterol- and sphingolipid-rich regions of the plasma membrane where it can impact on local Ca2 -stimulated AC8 activity [].
This entry represents the Ca2 -binding penta-EF-hand (PEF) domain found in CAPN2 (also known as Calpain 2). CAPN2 is a ubiquitously expressed Ca2 -dependent intracellular cysteine protease that contains a short N-terminal anchor helix, followed by a calpain cysteine protease (CysPc) domain, a C2-domain-like (C2L) domain, and a C-terminal Ca2 -binding penta-EF-hand (PEF) domain []. The catalytic subunit CAPN2 in complex with a regulatory subunit encoded by CAPNS1 forms an m-calpain heterodimer[]. CAPN2 acts as the key protease responsible for N-methyl-d-aspartic acid (NMDA)-induced cytoplasmic polyadenylation element-binding protein 3 (CPEB3) degradation in neurons []. It cleaves several components of the focal adhesion complex, such as FAK and talin, triggering disassembly of the complex at the rear of the cell []. The stimulation of CAPN2 activity is required for Golgi antiapoptotic proteins (GAAPs) to promote cleavage of FA kinase (FAK), cell spreading, and enhanced migration. calpain 2 is also involved in the onset of glial differentiation []. It regulates proliferation, survival, migration, and tumorigenesis of breast cancer cells through a PP2A-Akt-FoxO-p27(Kip1) signalling cascade []. Its expression is associated with response to platinum based chemotherapy, progression-free and overall survival in ovarian cancer []. Moreover, CAPN2 may play a role in fundamental mitotic functions, such as the maintenance of sister chromatid cohesion []. The activation of CAPN2 plays an essential role in hippocampal synaptic plasticity and in learning and memory []. In the eye, CAPN2, together with a lens-specific variant of CAPN3, is responsible for proteolytic cleavages of alpha and beta-crystallin. Overactivated alpha and beta-crystallin can lead to cataract formation []. Sometimes, CAPN2 compensates for loss of CAPN1, and both calpain isoforms are involved in AngII-induced aortic aneurysm formation []. The main phosphorylation sites in m-calpain are Ser50 and Ser369/Thr370.
PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium acting via calmodulin) [, ]. PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2 binding motifs referred to as EF hands [].
This domain of approximately 100 residues is conserved from plants to humans. It is an anticodon-binding domain of a prolyl-tRNA synthetase []. It is found in Lms12 and homologues. Lsm12 is a putative RNA-binding and regulation protein that might be involved in mRNA degradation or tRNA splicing []. Recently, it was demonstrated that it binds nicotinic acid adenine dinucleotide phosphate (NAADP) that confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca2 release []. Therefore, further studies of the potential crosstalk between NAADP signaling and RNA regulation are required.
RGS14 is a regulator of G protein signaling (RGS) protein. It regulates G protein nucleotide exchange and hydrolysis by acting as a GTPase-activating protein (GAP) through its RGS domain, and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif [, ]. Both domains of RGS14 target members of the Gialpha subclass []. It is a microtubule-associated protein that may modulate microtubule dynamics and spindle formation []and play an essential role during mammalian cell division []. RGS14 regulates the activation of alphaMbeta2 integrin during phagocytosis []. It is a key regulator of signalling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory [].
The troponin (Tn) complex regulates calcium-induced muscle contraction. Tn contains three subunits, Ca2 binding (TnC), inhibitory (TnI), and tropomyosin binding (TnT), which is required for Ca(2)-mediated activation of actomyosin ATPase activity [, ]. Three different troponin T genes that encode tissue-specific isoforms of subunit T have been found in mammals and birds, encoding cardiac (TNNT2), slow (TNNT1), and fast (TNNT3) skeletal muscle TnT isoforms [, , , ].This entry represents the fast (TNNT3) skeletal muscle TnT isoform. Defects in TNNT3 are a cause of distal arthrogryposis type 2B (DA2B); also known as arthrogryposis multiplex congenita, distal, type 2B (AMCD2B) [].
Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. In humans, the cPLA2 family contains six isoforms. Structural information of full length cPLA2alpha apo form, shows that it is composed of two domains; an N-terminal Ca2 + binding C2 domain and a C-terminal alpha/beta hydrolase core. This entry describes the N-terminal Ca2+ binding C2 domain which is composed of an eight-stranded antiparallel β-sandwich consisting of two four-stranded β-sheets. C2 domains are present in many lipid-binding proteins including Copines, CAPRI and Rabphilin-3A all of which are involved in membrane trafficking [].
SMP is a proposed lipid-binding module, ie a synaptotagmin-like mitochondrial-lipid-binding domain found in eukaryotes. The SMP domain has a β-barrel structure like protein modules in the tubular-lipid-binding (TULIP) superfamily. It dimerises to form an approximately 90-Angstrom-long cylinder traversed by a channel lined entirely with hydrophobic residues. The following two C2 domains then form arched structures flexibly linked to the SMP domain. The SMP domain is a lipid-binding domain that links the ER with other lipid bilayer-membranes within the cell [].This entry represents the SMP domain found in plant synaptotagmins []and extended synaptotagmins from metazoa. The extended synaptotagmins transport glycerolipids between the two bilayers via their lipid-harboring SMP domains and Ca2 + regulates their membrane tethering and lipid transport function [].
RGS14 is a regulator of G protein signaling (RGS) protein. It regulates G protein nucleotide exchange and hydrolysis by acting as a GTPase-activating protein (GAP) through its RGS domain, and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif [, ]. Both domains of RGS14 target members of the Gialpha subclass []. It is a microtubule-associated protein that may modulate microtubule dynamics and spindle formation []and play an essential role during mammalian cell division []. RGS14 regulates the activation of alphaMbeta2 integrin during phagocytosis []. It is a key regulator of signalling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory [].This entry represents the RGS domain of RGS14.
This entry represents Lsm12 and its homologues. Lsm12 is a putative RNA-binding and regulation protein that might be involved in mRNA degradation or tRNA splicing []. Recently, it was demonstrated that it binds nicotinic acid adenine dinucleotide phosphate (NAADP) that confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca2 release []. Therefore, further studies of the potential crosstalk between NAADP signaling and RNA regulation are required.Sm and Sm-like proteins of the Lsm (like Sm) domain family are generally involved in essential RNA-processing tasks []. All the LSM proteins are evolutionarily conserved in eukaryotes with an N-terminal Lsm domain to bind nucleic acids followed by a C-terminal region, some of which have a C-terminal methyltransferase domain.
This entry represents TPC2. It modulates neural differentiation of mouse embryonic stem cells []. It may also be involved in smooth muscle contraction []. Two-pore segment channels (TPCs or TPCNs) are located in membranes of acidic intracellular organelles (such as endo-lysosomes and plant vacuoles) and contain two putative pore-forming repeats. Each of these repeats contains six transmembrane segments and an intervening pore-loop, an architecture featured in voltage-gated channels []. Functional TPC channels are assembled from two TPC protein subunits forming a pore that conducts mainly Ca2 and Na. TPCs exist as three isoforms (TPC1-3): TPC1 and TPC2 are the most universal isoforms since TPC3 is absent from the genomes of many animals including those of human, mice, rats and flies [].
Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue α-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). Ca2 binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers [, , , , ].
Two-pore segment channels (TPCs or TPCNs) are located in membranes of acidic intracellular organelles (such as endo-lysosomes and plant vacuoles) and contain two putative pore-forming repeats. Each of these repeats contains six transmembrane segments and an intervening pore-loop, an architecture featured in voltage-gated channels []. Functional TPC channels are assembled from two TPC protein subunits forming a pore that conducts mainly Ca2 and Na. TPCs exist as three isoforms (TPC1-3): TPC1 and TPC2 are the most universal isoforms since TPC3 is absent from the genomes of many animals including those of human, mice, rats and flies []. This entry represents TPC1 from animals [, ]. TPC1 was first identified as an NAADP (nicotinic acid adenine dinucleotide phosphate)-regulated Ca2+ channel. Later it was shown to serve as a voltage-gated highly-selective Na+ channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) that senses pH changes and confers electrical excitability to organelles [, , , , ].
MCAfunc domain (MCAfunc) is located in the N-terminal region of a mechanosensitive channel protein MID1-COMPLEMENTING ACTIVITY (MCA). MCAfunc represents the provisionally advocated ARPK domain (Amino-terminal domain of Rice putative Protein Kinases), overlapping with the EF hand-like region at the N terminus []. In MCA proteins, MCAfunc has Ca2 influx activity and is proposed to be a functional domain of MCAs []. MCAfunc is exclusively observed in streptophytes and exists not only in MCA but also in E3 ubiquitin ligase-like proteins, ARO3-like proteins and and protein kinases. In the most basal plant lineage, charophytes, MCAfunc is only found in E3 ubiquitin ligase-like proteins and protein of presently unknown function, while MCA proteins are exclusively found in land plants, from bryophytes to angiosperms.
Calreticulin is a ubiquitous protein found in a wide range of species and in all nucleated cell types. It is an ancient and highly conserved protein with an exceptionally wide scope and variety of functions. Initially known as the high-affinity calcium-binding endoplasmic reticulum (ER) and sarcoplamic reticulum (SR) protein "calregulin", calreticulin is now known to associate with proteins in the cytoplasm, nucleus and extracellular compartment. Calreticulin is a major Ca2 -binding/storage chaperone residing in the ER lumen []. Molecular chaperones residing in the ER facilitate the folding and prevent the aggregation of newly synthesized proteins. Interaction between the molecular chaperone and the misfolded protein leads to the retention, retranslocation and eventual degradation of the misfolded protein by the proteasome after ubiquitination []. Calreticulin binds (buffers) Ca2 with high capacity and participates in folding newly synthesized proteins and glycoproteins. It is an important component of the calreticulin/calnexin cycle and quality control pathways in the ER []. Studies on calreticulin-deficient and calreticulin-transgenic mice revealed that calreticulin is a new cardiac embryonic gene and is essential during cardiac development [, ]. Calreticulin has also been characterised as an extracellular lectin, an intracellular mediator of integrin-mediated cell adhesion, an inhibitor of steroid hormone-regulated gene expression and a C1q-binding protein []. A proposed model of calreticulin domains includes a globular N-domain, a central proline-rich P-domain and an acidic C-domain. A detailed structure of the central P-domain was revealed by NMR studies, while a model of the globular N-domain of calreticulin is based on crystallographic data reported for the highly similar calnexin [].Calreticulin is also known as calregulin, Erp60, CRP55, CAB-63 and CaBP3 [].
This entry includes a group of EF-hand calcium-binding domain-containing proteins, including EFCAB3 and SPT21 (spermatogenesis-associated protein 21). The function of EFCAB3 is not clear. SPT21 is involved in the differentiation of haploid spermatids [].Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue α-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). Ca2 binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers [, , , , ].
Plant cell wall polysaccharides comprise the most abundant reservoir of organic carbon in the biosphere. The cellulosome is a large multienzymecomplex used by many anaerobic bacteria for the efficient degradation of plant-cell wall polysaccharides. The principal component of the cellulosome is a scaffolding subunit, a large enzyme-integrating protein, that contains cohesin modules (usually in multiple copies) for incorporation of thedifferent enzymes and other cellulosomal components. The enzymes contain a complementary type of module, the dockerin domain, that binds tenaciously to the cohesin modules of the scaffoldin subunit [, , , ].The dockerin domains consist of about 70 amino acid residues and contain two duplicated segments, each of about 22 amino acid residues. The first 12 residues of these duplicated sequences bear remarkable resemblance to the calcium-binding loop of the EF-hand motif, in which all thecalcium-binding residues (i.e., aspartic acids and asparagines) are highly conserved. The second halves of the duplicated sequences appear to form alpha helices. These helices would be analogous to the F helix of the EF-hand motif [, , , ].The dockerin domain comprises three α-helices. Helices H1 and H3, which are antiparallel to one another, and the two calcium-binding loops (Ca1 and Ca2) correspond to the tandem duplicated sequences that form the two F-hand motifs. A short loop region and helix H2 connect the F-hand motifs. The 12-residue Ca(2+)-binding loop of each motif coordinates one Ca2 ion in the typical pentagonal bipyramid configuration of EF-handCa2-binding proteins [, ].
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].This entry represents the double Cache domain 2 (dCache_2), which may be a result of single Cache domain 2 (sCache_2) duplication [].
This entry represents the N-terminal Cache-like domain of the alkaline phosphatase synthesis sensor protein PhoR. It covers part of the PAS-like fold that share a central five-stranded β-sheet of identical topology to other PAS domains [].Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].
This SCP-like extracellular protein domain is found in cysteine-rich secretory proteins (CRISPs). Involvement of CRISP in response to pathogens, fertilization, and sperm maturation have been proposed [, , ]. One member, Tex31 from the venom duct of Conus textile, has been shown to possess proteolytic activity sensitive to serine protease inhibitors []. SCP has also been proposed to be a Ca2 chelating serine protease. The Ca2-chelating function would fit with various signaling processes that members of this family, such as the CRISPs, are involved in, and is supported by sequence and structural evidence of a conserved pocket containing two histidines and a glutamate. It also may explain how helothermine, a toxic peptide secreted by the beaded lizard, blocks Ca++ transporting ryanodine receptors []. One member, DE or CRISP-1, has been shown to mediate gamete fusion by binding to the egg surface; a sequence motif in the SCP domain plays a role in that binding [].The SCP domain is also known as CAP domain []. The wider family of SCP containing proteins includes plant pathogenesis-related protein 1 (PR-1), CRISPs, mammalian cysteine-rich secretory proteins, which combine SCP with a C-terminal cysteine rich domain, and allergen 5 from vespid venom. It has been proposed that SCP domains may function as endopeptidases.
Plant cell wall polysaccharides comprise the most abundant reservoir of organic carbon in the biosphere. The cellulosome is a large multienzymecomplex used by many anaerobic bacteria for the efficient degradation of plant-cell wall polysaccharides. The principal component of the cellulosome is a scaffolding subunit, a large enzyme-integrating protein, that contains cohesin modules (usually in multiple copies) for incorporation of thedifferent enzymes and other cellulosomal components. The enzymes contain a complementary type of module, the dockerin domain, that binds tenaciously to the cohesin modules of the scaffoldin subunit [, , , ].The dockerin domains consist of about 70 amino acid residues and contain two duplicated segments, each of about 22 amino acid residues. The first 12 residues of these duplicated sequences bear remarkable resemblance to the calcium-binding loop of the EF-hand motif, in which all thecalcium-binding residues (i.e., aspartic acids and asparagines) are highly conserved. The second halves of the duplicated sequences appear to form alpha helices. These helices would be analogous to the F helix of the EF-hand motif [, , , ].The dockerin domain comprises three α-helices. Helices H1 and H3, which are antiparallel to one another, and the two calcium-binding loops (Ca1 and Ca2) correspond to the tandem duplicated sequences that form the two F-hand motifs. A short loop region and helix H2 connect the F-hand motifs. The 12-residue Ca(2+)-binding loop of each motif coordinates one Ca2 ion in the typical pentagonal bipyramid configuration of EF-handCa2-binding proteins [, ].
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].This entry represents the double Cache domain 3 (dCache_3), which may be a result of single Cache domain 3 (sCache_3) duplication [].
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].This entry represents the single Cache domain 2 (sCache_2), which contains the long N-terminal helix domain [].
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].This entry represents double cache domain 1, which covers the last three strands from the membrane distal PAS-like domain, the first two strands of the membrane proximal domain, and the connecting elements between the two domains [].
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].This entry represents the single cache domain 3 (sCache_3) [].
Cache is an extracellular domain that is predicted to have a role in small-molecule recognition in a wide range of proteins, including the animal dihydropyridine-sensitive voltage-gated Ca2 channel alpha-2delta subunit, and various bacterial chemotaxis receptors. The name Cache comes from CAlcium channels and CHEmotaxis receptors. The Cache domain, also known as the extracellular PAS domain, consists of an N-terminal part with three predicted strands and an α-helix, and a C-terminal part with a strand dyad followed by a relatively unstructured region. The N-terminal portion of the Cache domain containing the three predicted strands could form a sheet analogous to that present in the core of the PAS domain structure. Cache domains are particularly widespread in bacteria, such as Vibrio cholerae. The animal calcium channel alpha-2delta subunits might have acquired a part of their extracellular domains from a bacterial source []. The Cache domain appears to have arisen from the GAF-PAS fold, despite their divergent functions [, ].This entry represents a type of Cache domain that likely originated asa fusion of sCache_3 and sCache_2 domains [].
The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily proteins are found in a wide range of organisms, including prokaryotes []and non-vertebrate eukaryotes [], The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. Members are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumour suppressor or pro-oncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilisation. The overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters the target specificity and, thus, the biological consequences []. The Ca2-chelating function []would fit with the various signalling processes (e.g. the CRISP proteins) that members of this family are involved in, and also the sequence and structural evidence of a conserved pocket containing two histidines and a glutamate. It also may explain how blocks the Ca2 transporting ryanodine receptors. The CAP domain forms a unique 3 layer α-β-α fold with some, though not all, of the structural elements found in proteases [].
Many calcium-binding proteins belong to the same evolutionary family and share a type of calcium-binding domain known as the EF-hand. This type of domain consists of a twelve residue loop flanked on both sides by a twelve residue α-helical domain. In an EF-hand loop the calcium ion is coordinated in a pentagonal bipyramidal configuration. The six residues involved in the binding are in positions 1, 3, 5, 7, 9 and 12; these residues are denoted by X, Y, Z, -Y, -X and -Z. The invariant Glu or Asp at position 12 provides two oxygens for liganding Ca (bidentate ligand). Ca2 binding induces a conformational change in the EF-hand motif, leading to the activation or inactivation of target proteins. EF-hands tend to occur in pairs or higher copy numbers [, , , , ].This signature pattern includes the complete EF-hand loop as well as the first residue which follows the loop and which seem to always be hydrophobic. Note: positions 1 (X), 3 (Y) and 12 (-Z) are the most conserved. The 6th residue in an EF-hand loop is, inmost cases a Gly, but the number of exceptions to this 'rule' has gradually increased, therefore, this signature pattern includes all the different residues which have been shown to exist in this position in functional Ca-binding sites. The pattern is known, in some cases, to miss one of the EF-hand regions in some proteins with multiple EF-hand domains.
The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily proteins are found in a wide range of organisms, including prokaryotes []and non-vertebrate eukaryotes [], The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. Members are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumour suppressor or pro-oncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilisation. The overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters the target specificity and, thus, the biological consequences []. The Ca2-chelating function []would fit with the various signalling processes (e.g. the CRISP proteins) that members of this family are involved in, and also the sequence and structural evidence of a conserved pocket containing two histidines and a glutamate. It also may explain how blocks the Ca2 transporting ryanodine receptors. This entry represents the CAP domain common to all members of the CAP superfamily. The CAP domain forms a unique 3 layer α-β-α fold with some, though not all, of the structural elements found in proteases [].
The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily proteins are found in a wide range of organisms, including prokaryotes []and non-vertebrate eukaryotes [], The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. Members are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumour suppressor or pro-oncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilisation. The overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters the target specificity and, thus, the biological consequences []. The Ca2-chelating function []would fit with the various signalling processes (e.g. the CRISP proteins) that members of this family are involved in, and also the sequence and structural evidence of a conserved pocket containing two histidines and a glutamate. It also may explain how blocks the Ca2 transporting ryanodine receptors. This entry represents a subgroup of the CAP domains found only in bacteria capable of endospore formation. Proteins containing this domain include YkwD of Bacillus subtilis. This domain is generally found at the C-terminal region of these proteins, while the N-terminal region sometimes contains a domain homologous to the spore coat assembly protein SafA ().
Members of the mas-related receptor family (also known as oncogene-like MAS and mas-related G-protein coupled receptor MRG) have been implicated in the development, regulation and function of nociceptive neurons, specifically in the modulation of pain. Most members are orphaned, with no endogeneous ligand identified. Of the human mas-related GPCRs, four (MRGPRD, MRGPRE, MRGPRF and MRGPRG) are also found in rodents, whereas MRGPRX1, MRGPRX2, MRGPRX3 and MRGPRX4 are found exclusively in primates. Certain rodent MRGs have been reported to respond to adenine []and to RF-amide peptides, including neuropeptide FF [, ], but the relevance of these findings to man is unclear. MRGs are expressed predominantly in small diameter sensory neurons of the dorsal root ganglia, where there is emerging evidence that they may be mediators of histamine-independent itch [, ].This entry represents Mas-related G protein-coupled receptor X1 and X2.Mas-related G protein-coupled receptor X1 (MRGPRX1) is thought to be involved with nociceptor function and development, and in the modulation of pain. The receptor is currently orphaned, no specific endogenous ligand having been identified. However, it may potently be activated by enkephalins: BAM22 evokes a large and dose-dependent release of intracellular calcium in cells stably transfected with the receptor []. Mas-related G protein-coupled receptor X2 (MRGPRX2) is thought to be involved with nociceptor function and development, and directly involved in the modulation of pain. The receptor is currently orphaned, no specific endogenous ligand having been identified. However, it may be activated by neuropeptides: stimulation by cortistatin-14 in receptor-expressing cells potently increases intracellular Ca2 [, ]. MRGPRX2 is also thought to be a human PAMP-12 receptor that regulates catecholamine secretion from adrenal glands [].
P2X purinoceptors are cell membrane ion channels, gated by adenosine 5'-triphosphate (ATP) and other nucleotides; they have been found to be widely expressed on mammalian cells, and, by means of their functional properties, can be differentiated into three sub-groups. The first group is almost equally well activated by ATP and its analogue alpha,betamethylene-ATP, whereas, the second group is not activated by the latter compound. A third type of receptor (also called P2Z) is distinguished by the fact that repeated or prolonged agonist application leads to the opening of much larger pores, allowing large molecules to traverse the cell membrane. This increased permeability rapidly leads to cell death, and lysis.Molecular cloning studies have identified seven P2X receptor subtypes, designated P2XR1-P2XR7, however, P2X1R, P2X2R, P2X3R, P2X4R, and P2X7R are functional []. These receptors are proteins that share 35-48% amino acid identity, and possess two putative transmembrane (TM) domains, separated by a long (~270 residues) intervening sequence, which is thought to form an extracellular loop. Around 1/4 of the residues within the loop are invariant between the cloned subtypes, including 10 characteristic cysteines.Studies of the functional properties of heterologously expressed P2X receptors, together with the examination of their distribution in native tissues, suggests they likely occur as both homo- and hetero multimers in vivo [, ]. Stimulation of these receptors induces changes in intracellular ion homeostasis leading to multiple key responses crucial for initiation, propagation, and resolution of inflammation []. The P2X7 subtype has an important role in the activation of lymphocyte, granulocyte, macrophage and dendritic cell responses and, therefor, it may be a promising target for anti-inflammatory therapies.This entry represents the intracellular domain found at the C-terminal domain of P2X7 (also known as P2Z receptor). P2X7 receptor has different functional properties from those of P2X1-P2X6. Key properties of the current produced are little rectification or desensitisation, and strong potentiation of responses when the concentration of extracellular Ca2 and/or Mg2 are reduced. It is also found to be relatively insensitive to ATP. In certain studies, prolonged activation of expressed P2X7 receptors causes cell permeabilization, and lysis. This domain is critical for the receptor to initiate apoptosis and not undergo desensitization. It shows a globular structure and is shaped like a wedge with three β-strands forming an antiparallel β-sheet followed by eight α-helices separated by loops that form a helical bundle [].
This entry represents Pentaxins and its related proteins such as CRP (C-reactive protein) and SAP (serum amyloid P component protein) []. This entry also includes adhesion G-protein coupled receptors D2 and G6 from humans.Pentraxins (or pentaxins) [, ]are a family of proteins which show, under electron microscopy, a discoid arrangement of five noncovalently bound subunits. Proteins of the pentraxin family are involved in acute immunological responses []. Three of the principal members of the pentraxin family are serum proteins and Ca2 dependent: namely, C-reactive protein (CRP) [], serum amyloid P component protein (SAP) [], and female protein (FP) []. CRP binds to ligands containing phosphocholine, SAP binds to amyloid fibrils, DNA, chromatin, fibronectin, C4-binding proteins and glycosaminoglycans.CRP is expressed during acute phase response to tissue injury or inflammation in mammals. The protein resembles antibody and performs several functions associated with host defence: it promotes agglutination, bacterial capsular swelling and phagocytosis, and activates the classical complement pathway through its calcium-dependent binding to phosphocholine. CRPs have also been sequenced in an invertebrate, Limulus polyphemus (Atlantic horseshoe crab), where they are a normal constituent of the hemolymph [].SAP is a vertebrate protein that is a precursor of amyloid component P. It is found in all types of amyloid deposits, in glomerular basement menbrane and in elastic fibres in blood vessels. SAP binds to various lipoprotein ligands in a calcium-dependent manner, and it has been suggested that, in mammals, this may have important implications in atherosclerosis and amyloidosis [].FP is a SAP homologue found in Mesocricetus auratus (golden hamster). The concentration of this plasma protein is altered by sex steroids and stimuli that elicit an acute phase response."Long"pentraxins have N-terminal extensions to the common pentraxin domain []; one group, the neuronal pentraxins, may be involved in synapse formation and remodeling, and they may also be able to form heteromultimers []. Pentraxin proteins expressed in the nervous system are neural pentraxin I (NPI) and II (NPII) []. NPI and NPII are homologous and can exist within one species. It is suggested that both proteins mediate the uptake of synaptic macromolecules and play a role in synaptic plasticity. Apexin, a sperm acrosomal protein, is a homologue of NPII found in Cavia porcellus (Guinea pig) [].PTX3 is a long pentraxin that provides defence against infectious agents and plays several functions in tissue repair and regulation of cancer-related inflammation [].
