ARHGAP33 (also known as TCGAP) is a Rho GTPase-activating protein involved in insulin-stimulated glucose transport []. It is widely expressed in the brain where it is involved in regulating the outgrowth of axons and dendrites and is regulated by the protein tyrosine kinase Fyn []. It also plays a role in TrkB trafficking, which is essential for synapse development [].
Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells []. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's []and Parkinson's diseases []. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury [].Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR []. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5 []. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Tom1 (target of Myb 1) and its related proteins (Tom1L1 and Tom1L2) constitute a protein family and share an N-terminal VHS (Vps27p/Hrs/Stam) domain followed by a GAT (GGA and Tom1) domain.VHS domains are found at the N termini of select proteins involved in intracellular membrane trafficking and are often localized to membranes. The three dimensional structure of human TOM1 VHS domain reveals eight helices arranged in a superhelix. The surface of the domain has two main features: (1) a basic patch on one side due to several conserved positively charged residues on helix 3 and (2) a negatively charged ridge on the opposite side, formed by residues on helix 2 []. The basic patch is thought to mediate membrane binding.It was demonstrated that the GAT domain of both Tom1 and Tom1L1 binds ubiquitin, suggesting that these proteins might participate in the sorting of ubiquitinated proteins into multivesicular bodies (MVB) []. Moreover, Tom1L1 interacts with members of the MVB sorting machinery. Specifically, the VHS domain of Tom1L1 interacts with Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate), whereas a PTAP motif, located between the VHS and GAT domains of Tom1L1, is responsible for binding to TSG101 (tumour susceptibility gene 101). Myc epitope-tagged Tom1L1 is recruited to endosomes following Hrs expression. In addition, Tom1L1 possesses several tyrosine motifs at the C-terminal region that mediate interactions with members of the Src family kinases and other signalling proteins such as Grb2 and p85. Expression of a constitutively active form of Fyn kinase promotes the recruitment of Tom1L1 to enlarged endosomes. It is proposed that Tom1L1 could act as an intermediary between the signalling and degradative pathways [].Over expression of Tom1 suppresses activation of the transcription factors NF-kappaB and AP-1, induced by either IL-1beta or tumour necrosis factor (TNF)-alpha, and the VHS domain of Tom1 is indispensable for this suppressive activity. This suggests that Tom1 is a common negative regulator of signalling pathways induced by IL-1beta and TNF-alpha [].
Prion protein (PrP-c) [, , ]is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal and infected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) [].The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process. In humans, PrP is a 253 amino acid protein, which has a molecular weight of 35-36kDa. It has two hexapeptides and repeated octapeptides at the N terminus, a disulphide bond and is associated at the C terminus with a GPI, which enables it to anchor to the external part of the cell membrane. The secondary structure of PrP-c is mainly composed of α-helices, whereas PrP-sc is mainly β-sheets: transconformation of α-helices into β-sheets has been proposed as the structural basis by which PrP acquires pathogenicity in TSEs. The three-dimensional structures shows the protein to be made of a globular domain which includes three α-helices and two small antiparallel β-sheet structures, and a long flexible tail whose conformation depends on the biophysical parameters of the environment. Crystals of the globular domain of PrP have recently been obtained; their analysis suggests a possible dimerisation of the protein through the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulphide bond.
This entry represents the C-terminal β-ribbon domain superfamily found in prion proteins []and the prion-like Doppel proteins []. This domain has a beta-α-β-alpha(2) structure that contains an antiparallel β-ribbon.Prion protein (PrP-c) [, , ]is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal and infected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) [].The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process. In humans, PrP is a 253 amino acid protein, which has a molecular weight of 35-36kDa. It has two hexapeptides and repeated octapeptides at the N terminus, a disulphide bond and is associated at the C terminus with a GPI, which enables it to anchor to the external part of the cell membrane. The secondary structure of PrP-c is mainly composed of α-helices, whereas PrP-sc is mainly β-sheets: transconformation of α-helices into β-sheets has been proposed as the structural basis by which PrP acquires pathogenicity in TSEs. The three-dimensional structures shows the protein to be made of a globular domain which includes three α-helices and two small antiparallel β-sheet structures, and a long flexible tail whose conformation depends on the biophysical parameters of the environment. Crystals of the globular domain of PrP have recently been obtained; their analysis suggests a possible dimerisation of the protein through the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulphide bond.
This entry represents the C-terminal β-ribbon domain found in prion proteins []and the prion-like Doppel proteins []. This domain has a beta-α-β-alpha(2) structure that contains an antiparallel β-ribbon.Prion protein (PrP-c) [, , ]is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal andinfected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) [].The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process. In humans, PrP is a 253 amino acid protein, which has a molecular weight of 35-36kDa. It has two hexapeptides and repeated octapeptides at the N terminus, a disulphide bond and is associated at the C terminus with a GPI, which enables it to anchor to the external part of the cell membrane. The secondary structure of PrP-c is mainly composed of α-helices, whereas PrP-sc is mainly β-sheets: transconformation of α-helices into β-sheets has been proposed as the structural basis by which PrP acquires pathogenicity in TSEs. The three-dimensional structures shows the protein to be made of a globular domain which includes three α-helices and two small antiparallel β-sheet structures, anda long flexible tail whose conformation depends on the biophysical parameters of the environment. Crystals of the globular domain of PrP have recently been obtained; their analysis suggests a possible dimerisation of the protein through the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulphide bond.
Prion protein (PrP-c) [, , ]is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal and infected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) [].The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process. The N-terminal domain of the prion protein includes the N-terminal, positively charged polybasic region and the octapeptide repeat (OR) region The latter, represented by this entry, has been shown to bind to copper, which has been related with novel inter-domain interaction. Both are important for the convesion of PrP-c into PrP-sc [, , , ]. The number and organization of the repeats varies and is thought to be related to phenotypic variation. In this way, the insertion of four or more octapeptide repeats has been proved to be pathogenic, while smaller repeat insertions have an unclear pathogenicity. In any case, the presence of this insertion repeat in the protein may slightly increase risk of developing sporadic CJD [].
