VHS (Vps27/Hrs/STAM) domain of TOM1-like protein 1; TOM1-like protein 1 (Tom1L1) is also called Src-activating and signaling molecule protein (Srcasm). It is a member of the Tom1 (Target of myb1) subfamily, characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. They are novel regulators for post-Golgi trafficking and signaling. Tom1L1 has been implicated in multivesicular body (MVB) formation, viral egress from the cell, and cytokinesis. Its amplification enhances the metastatic progression of ERBB2-positive breast cancers. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  14 SVGHLIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVK 93
Cdd:cd16997     1 SVGHLIEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRISKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1007382088  94 KEFVKENLVKLLNPRYNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKG 150
Cdd:cd16997    81 KEFVKDVLVKLLNPRYNLPVDLQNKILNFIMTWAQGFQGGVDVSEVKEVYLDLVKKG 137

VHS (Vps27/Hrs/STAM) domain of TOM1-like protein 1; TOM1-like protein 1 (Tom1L1) is also called Src-activating and signaling molecule protein (Srcasm). It is a member of the Tom1 (Target of myb1) subfamily, characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. They are novel regulators for post-Golgi trafficking and signaling. Tom1L1 has been implicated in multivesicular body (MVB) formation, viral egress from the cell, and cytokinesis. Its amplification enhances the metastatic progression of ERBB2-positive breast cancers. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  14 SVGHLIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVK 93
Cdd:cd16997     1 SVGHLIEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRISKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1007382088  94 KEFVKENLVKLLNPRYNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKG 150
Cdd:cd16997    81 KEFVKDVLVKLLNPRYNLPVDLQNKILNFIMTWAQGFQGGVDVSEVKEVYLDLVKKG 137

Domain present in VPS-27, Hrs and STAM; Unpublished observations. Domain of unknown function.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088   15 VGHLIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISkNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVKK 94
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLINSTPDGPKDAVRLLKKRLN-NKNPHVALLALTLLDACVKNCGSKFHLEVASK 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1007382088   95 EFVkENLVKLLNPRYNLPLdIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKG 150
Cdd:smart00288  80 EFL-NELVKLIKPKYPLPL-VKKRILELIQEWADAFKNDPDLSQIVDVYDLLKKKG 133

GAT domain; The GAT domain is responsible for binding of GGA proteins to several members of the ARF family including ARF1 and ARF3. The GAT domain stabilizes membrane bound ARF1 in its GTP bound state, by interfering with GAP proteins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1007382088 213 KMNVRVMSAILMENTPGSEnhEDIELLQKLYKTGREMQERIMDLLV-VVENEDVTVELIQVNEDLNNAILGYERFTRN 289
Cdd:pfam03127   1 RNNAKLLNEMLSSTDPDEE--LDNELIKELYERCKSAQPKIQKLIEeTSDEDDLLAELLQLNDDLNNVLERYERLKKG 76

VHS (Vps27/Hrs/STAM) domain of TOM1-like protein 1; TOM1-like protein 1 (Tom1L1) is also called Src-activating and signaling molecule protein (Srcasm). It is a member of the Tom1 (Target of myb1) subfamily, characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. They are novel regulators for post-Golgi trafficking and signaling. Tom1L1 has been implicated in multivesicular body (MVB) formation, viral egress from the cell, and cytokinesis. Its amplification enhances the metastatic progression of ERBB2-positive breast cancers. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  14 SVGHLIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVK 93
Cdd:cd16997     1 SVGHLIEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRISKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1007382088  94 KEFVKENLVKLLNPRYNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKG 150
Cdd:cd16997    81 KEFVKDVLVKLLNPRYNLPVDLQNKILNFIMTWAQGFQGGVDVSEVKEVYLDLVKKG 137

canonical GAT domain found in target of Myb-like protein 1 (Tom1L1); Tom1L1, also called Src-activating and signaling molecule protein (Srcasm), was identified as a substrate of the Src family of protein kinases. It is tyrosine-phosphorylated by Src family kinases and modulates growth factor and Src-mediated signaling pathways. It also plays a potential role in endosomal sorting and ligand-stimulated endocytosis of EGF receptors (EGFR). Tom1L1 is predominantly present in the cytosol and can interact with Toll-interacting protein (Tollip), Hrs or TSG101, clathrin, and ubiquitinated proteins. It contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain, a GAT (GGA and TOM1) domain, and a C-terminal clathrin-binding region, both of which are conserved in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs). It interacts with Tollip through their GAT domain and recuits clathrin onto endosomes through their C-terminal region. However, in the C-terminal clathrin-binding region, Tom1 and Tom1L2 are similar to each other, but distinguishable from Tom1L1. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088 199 PEQIGKLHSELDMVKMNVRVMSAILMENTPGSENHEDIELLQKLYKTGREMQERIMDLLVVVENEDVTVELIQVNEDLNN 278
Cdd:cd14237     1 PEQIGKLYSELDIVKMNVRVMSAILLENTPGAENPEDMELLEKLYKTCREMQERIMKLLETVENEDVIIELIQVNDDLNN 80

                          90
                  ....*....|..
gi 1007382088 279 AILGYERFTRNQ 290
Cdd:cd14237    81 VFLRHERFSRNR 92

VHS (Vps27/Hrs/STAM) domain of Target of Myb protein 1; Tom1 (Target of myb1 - retroviral oncogene) is a novel negative regulator of interleukin-1 and tumor necrosis factor-induced signaling pathways. It also plays important roles in protein-degradation systems in Alzheimer's disease pathogenesis. Tom1 contains VHS and GAT domains in the N-terminal and central region, respectively. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting. The VHS domain of Tom1 is essential for its function as a negative regulator.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  15 VGHLIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVKK 94
Cdd:cd16995     2 VGQRIEKATDGSLQSEDWGLNMEICDIINETEEGPKDAIRAIKKRIVGNKNFREVMLALTVLETCVKNCGHRFHVLVASQ 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1007382088  95 EFVKENLVKLLNPRYNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKG 150
Cdd:cd16995    82 DFVEGVLVKTILPKNNPPAIVHDKVLNLIQAWADAFRSSPDLTGVVTVYEDLRRKG 137

canonical GAT domain found in target of myb protein 1 (Tom1) protein family; Tom1 and its related proteins, Tom1L1 and Tom1L2, form a protein family sharing an N-terminal VHS (Vps27p/Hrs/STAM)-domain followed by a GAT (GGA and TOM1) domain, both of which are also conserved in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs). In contrast to GGAs, the Tom1 family proteins bind to ubiquitin, ubiquitinated proteins, and Toll-interacting protein (Tollip) through its GAT domain, but do not associate with Arf GTPases through its GAT domain nor with acidic cluster-dileucine sequences through its VHS domain. In addition, the Tom1 family proteins recruit clathrin onto endosomes through their C-terminal region. In their C-terminal clathrin-binding regions, Tom1 and Tom1L2 are similar to each other, but distinguishable from Tom1L1. The yeast S. cerevisiae does not contain homologous proteins of the Tom1 family. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088 202 IGKLHSELDMVKMNVRVMSAILMENTPGSENHEDIELLQKLYKTGREMQERIMDLLVVVENEDVTVELIQVNEDLNNAIL 281
Cdd:cd14233     1 IAKLRSELDVVEGNLKVMSEMLTELVPGQENPDDLELLQELNSTCRAMQQRVVELISQVSNEEVTEELLRVNDDLNNVFL 80

                  ....*..
gi 1007382088 282 GYERFTR 288
Cdd:cd14233    81 RYERFER 87

VHS (Vps27/Hrs/STAM) domain family; The VHS domain is present in Vps27 (Vacuolar Protein Sorting), Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (Signal Transducing Adaptor Molecule). It has a superhelical structure similar to that of the ARM (Armadillo) repeats and is present at the N-termini of proteins involved in intracellular membrane trafficking. There are four general groups of VHS domain containing proteins based on their association with other domains. The first group consists of proteins of the STAM/EAST/Hbp family, which has the domain composition of VHS-SH3-ITAM. The second consists of proteins with a FYVE domain C-terminal to VHS. The third consists of GGA proteins with a domain composition of VHS-GAT (GGA and TOM)-GAE (Gamma-Adaptin Ear) domain. The fourth consists of proteins with a VHS domain alone or with domains other than those mentioned above. In GGA proteins, VHS domains are involved in cargo recognition in trans-Golgi, thereby having a general membrane targeting/cargo recognition role in vesicular trafficking.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  18 LIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRIsKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVKKEFV 97
Cdd:cd03561     4 LVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRL-QSKNPKVQLLALTLLETLVKNCGAPFHSEVASRDFL 82

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 1007382088  98 KEnLVKLLNpRYNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDL 146
Cdd:cd03561    83 QE-LVKLVK-KKKTSPEVREKALALIQEWAEAFQGDGRLPLFYDTYQQL 129

VHS (Vps27/Hrs/STAM) domain of metazoan GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) proteins; GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) comprises a subfamily of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. Jawed vertebrates contain as many as three GGA proteins: GGA1, GGA2, and GGA3. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  18 LIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRIsKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVKKEFV 97
Cdd:cd03567     5 LLNKATNPFNTEEDWEAIDAFCDRVNKEPEGPQIAVRLLAHKI-QSPNEKEALRALTVLEACVKNCGPRFHSEVGKFRFL 83

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  98 KEnLVKLLNPRYN---LPLDIQNRILNFIKTWSQGFPggvDVSEVKEVYLDLVKKGVQFP 154
Cdd:cd03567    84 NE-LIKLVSPKYLgnrTPEEVKQKIIELLYSWTRSLP---HEPKIKEAYDMLKKQGIIKE 139

VHS (Vps27/Hrs/STAM) domain of Vacuolar protein sorting-associated protein 27; Vacuolar protein sorting-associated protein 27 (Vps27 or Vps27p) is also called Golgi retention defective protein 11, and is the yeast homolog of Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate). Together with class E vacuolar protein-sorting machinery protein HSE1, it comprises the ESCRT-0 complex, the sorting receptor for ubiquitinated cargo proteins at the multivesicular body (MVB). The complex directly binds to ubiquitinated transmembrane proteins and recruits both ubiquitin ligases and deubiquitinating enzymes. It is also required the efficient recycling of late Golgi proteins including the carboxypeptidase Y (CPY) sorting receptor, Vps10. Vps27 contain similar domains and motifs to Hrs; it contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, two Ubiquitin-Interacting Motifs (UIMs), a GAT (GGA and TOM) domain, two a P(S/T)XP motifs that recruit ESCRT-I, and a short peptide motif near the C-terminus that recruits clathrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  18 LIEKAT--FAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRI-SKNYNhkeIQL-TLSLIDMCVQNCGPSFQSLIVK 93
Cdd:cd16979     6 LIEKATseSIPNGEEDLALALEISDLIRSKSVPPKDAMRSLKKRIlHKNPN---VQLlALKLTDVCVKNGGDHFLVEIAS 82

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1007382088  94 KEFVkENLVKLL-----NPrynlplDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKGVQFP 154
Cdd:cd16979    83 REFM-DNLVSLIrstgvNP------EVKEKILRLIQEWALAFKSKSQLSYVVEVYKKLKSEGIEFP 141

VHS (Vps27/Hrs/STAM) domain of Class E vacuolar protein-sorting machinery protein HSE1; Class E vacuolar protein-sorting machinery protein HSE1, together with Vps27, comprise the ESCRT-0 complex, the sorting receptor for ubiquitinated cargo proteins at the multivesicular body (MVB). The complex directly binds to ubiquitinated transmembrane proteins and recruits both ubiquitin ligases and deubiquitinating enzymes. It is also required the efficient recycling of late Golgi proteins including the carboxypeptidase Y (CPY) sorting receptor, Vps10. Similar to metazoan STAMs, HSE1 contain: an N-terminal VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats; a Ubiquitin-Interacting Motif (UIM); a SH3 (Src Homology 3) domain, a well-established protein-protein interaction domain; and a GAT (GGA and TOM) domain, which is essential for the normal sorting function of HSE1.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  18 LIEKATFAGVQTEDWGQFMHICDIIN-TTQDGPKDAVKALKKRI-SKNYNhkeIQL-TLSLIDMCVQNCGPSFQSLIVKK 94
Cdd:cd16978     4 LIIKATDETLTSENWQYILDVCDKVNsDPEDGAREAIAAIQKRLqHRNAN---VQLrSLSLADALAKNCGSRLHQEISSR 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1007382088  95 EFVKENLVKLLNPryNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKG 150
Cdd:cd16978    81 SFTQTLLRLINDR--TTHATVKKRILELIKQLSDSFKSDPSLGLMSDTYDQLKSKY 134

VHS (Vps27/Hrs/STAM) domain of Signal Transducing Adapter Molecule 2; Signal Transducing Adapter Molecule 2 (STAM2) is also called EAST (EGFR-Associated protein with SH3 and TAM domain) and Hbp (Hrs-binding protein). It is highly expressed in neurons, where it is localized in the nucleus. STAM (Signal Transducing Adaptor Molecule) subfamily members have at their N-termini a VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats, followed by a Ubiquitin-Interacting Motif (UIM) and a SH3 (Src Homology 3) domain, which is a well-established protein-protein interaction domain, and a GAT (GGA and TOM) domain. At the C-termini of most vertebrate STAMS, an Immunoreceptor Tyrosine-based Activation Motif (ITAM) is present, which mediates the binding of HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in endocytic and exocytic machineries. STAM is a component of the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery and together with Hrs, functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  19 IEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQlTLSLIDMCVQNCGPSFQSLIVKKEFVK 98
Cdd:cd16999     5 VEKATNEYNTSEDWSLIMDICDKVGSTPNGAKDCLKAIMKRVNHKVPHVALQ-ALTLLGACVSNCGKIFHLEVCSRDFAT 83

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1007382088  99 EnLVKLLNPRYNlPlDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKGVQFPPS 156
Cdd:cd16999    84 E-VRAVIKNKAH-P-KVCEKLKALMVEWSEEFQKDPQFSLISATIKSLKEEGITFPPA 138

VHS (Vps27/Hrs/STAM) domain of Hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs; Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) plays a role in at least three vesicle trafficking events: exocytosis, endocytosis, and endosome to lysosome trafficking. Hrs is involved in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane. Together with STAM or STAM2, it comprises the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery, which functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Hrs contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, a Double Ubiquitin-Interacting Motif (DUIM), a P(S/T)XP motif that recruit ESCRT-I, a GAT (GGA and TOM) domain, and a short peptide motif near the C-terminus that recruits clathrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  18 LIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRI-SKNYNhkeIQL-TLSLIDMCVQNCGPSFQSLIVKKE 95
Cdd:cd03569     6 LLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLnDQNPH---VALyALQVLESVVKNCGTPVHDEVATKE 82

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1007382088  96 FVKE--NLVKLLNPRynlplDIQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLVKKGVQFP 154
Cdd:cd03569    83 FMEElrDLVKTTTSE-----NVRNKILELIQAWAHAFRNEPKYKIVQDTYNIMKMEGYKFP 138

VHS (Vps27/Hrs/STAM) domain of LAS seventeen-binding protein 5; LAS seventeen-binding protein 5 (LAS17-binding protein 5, Lsb5, or Lsb5p) localizes to the plasma membrane and plays a role in endocytosis in yeast. It interacts with actin regulators Sla1p and Las17p, ubiquitin, and Arf3p, coupling actin dynamics to membrane trafficking processes. Lsb5p contains an N-terminal VHS domain and a GAT (GGA and TOM) domain. The VHS domain has a superhelical structure similar to the structure of ARM (Armadillo) repeats. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  18 LIEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISknYNHKEIQL-TLSLIDMCVQNCGPSFQSLIVKKEF 96
Cdd:cd16980     4 TIERLTSSEYEEEDWSLVLELCELINLIESGAKEAARALRKKLK--YGNPHQQLrALTLLDLLVENGGKKFQAQFASDKK 81

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1007382088  97 VKEnLVKLLNPRYNLPLDIQNRILNFIKTWSQGFPGGVDVSEVKEVY 143
Cdd:cd16980    82 LED-LLRLIASDPSTDPKVRKKLLELLGGWAYEFKGDPGLSGIASLY 127

VHS (Vps27/Hrs/STAM) domain of ADP-ribosylation factor-binding protein GGA1; ADP-ribosylation factor-binding protein GGA1 (Golgi-localized, Gamma-ear-containing, Arf-binding 1) is also called Gamma-adaptin-related protein 1. It is expressed in human brain and affects the generation of amyloid beta-peptide, and may be involved in the pathogenesis of Alzheimer disease. It is a member of the GGA subfamily, which is comprised of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  19 IEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQlTLSLIDMCVQNCGPSFQSLIVKKEFVK 98
Cdd:cd17009     6 INRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQ-ALTVLETCMKSCGKRFHDEVGKFRFLN 84

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1007382088  99 EnLVKLLNPRY---NLPLDIQNRILNFIKTWSQGFPGGVDVSevkEVYLDLVKKGV 151
Cdd:cd17009    85 E-LIKVVSPKYlgsRTPEKVKNKILELLYSWTVGLPEEVKIA---EAYQMLKKQGI 136

VHS (Vps27/Hrs/STAM) domain of ADP-ribosylation factor-binding protein GGA2; ADP-ribosylation factor-binding protein GGA2 (Golgi-localized, Gamma-ear-containing, Arf-binding 2) is also called Gamma-adaptin-related protein 2 and VHS domain and ear domain of gamma-adaptin (Vear). It is a member of the GGA subfamily, which is comprised of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088  19 IEKATFAGVQTEDWGQFMHICDIINTTQDGPKDAVKALKKRIsKNYNHKEIQLTLSLIDMCVQNCGPSFQSLIVKKEFVK 98
Cdd:cd17010     6 LNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKI-QSPQEREALHALTVLEMCMNNCGERFHSEVAKFRFLN 84

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1007382088  99 EnLVKLLNPRYN---LPLDIQNRILNFIKTWSQGFPGGVdvsEVKEVYLDLVKKGV 151
Cdd:cd17010    85 E-LIKVLSPKYLgtwSSEKVKSRVIEVLFSWTVWLPEEV---KIRDAYQMLKKQGI 136

GAT domain found in eukaryotic GGAs, metazoan Tom1-like proteins, metazoan STAMs, fungal Vps27, and similar proteins; The GAT (GGA and Tom1) domain superfamily includes the canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins (GGAs) from eukaryotes, myb protein 1 (Tom1)-like proteins from metazoa, and LAS seventeen-binding protein 5 (Lsb5p)-like proteins from fungi. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin. GGAs, also called Golgi-localized gamma-ear-containing Arf-binding proteins, belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. GGAs play important roles in ubiquitin-dependent sorting of cargo proteins both in biosynthetic and endocytic pathways. Tom1 and its related proteins, Tom1L1 and Tom1L2, form a protein family sharing an N-terminal VHS-domain followed by a GAT domain. Tom1 family proteins bind to ubiquitin, ubiquitinated proteins, and Toll-interacting protein (Tollip) through its GAT domain. They do not associate with either Arf GTPases through its GAT domain nor with acidic cluster-dileucine sequences through its VHS domain. The GAT domain superfamily also includes the non-canonical GAT domain found in several components of the ESCRT-0 complex, including signal transducing adapter molecules (STAMs) and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) from metazoa, as well as vacuolar protein sorting-associated protein 27 (Vps27) and class E vacuolar protein-sorting machinery protein Hse1 from fungi. Hrs, together with STAM, forms a Hrs/STAM core complex. Vps27, together with Hse1, forms a Vps27/Hse1 core complex. Those complexes consist of two intertwined GAT domains, each consisting of two helices from one subunit, and one from the other subunit. The intertwined GAT heterodimer acts as a scaffold for binding of ubiquitinated cargo proteins and coordinating ubiquitination and deubiquitination reactions that regulate sorting.

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gi 1007382088 210 DMVKMNVRVMSAILMENTPGSENHEDIELLQKLYKTGREMQERIMDLLVVVENEDVTVELIQVNEDLNNAILGYERF 286
Cdd:cd12930     1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLNDKADDQKYNTLLE*NDNLSEV*NIYDRL 77

canonical GAT domain found in metazoan ADP-ribosylation factor (Arf)-binding proteins (GGAs); GGAs, also called Golgi-localized gamma-ear-containing Arf-binding proteins, belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. Moreover, GGAs play important roles in ubiquitin-dependent sorting of cargo proteins both in biosynthetic and endocytic pathways. Three GGAs (GGA1, GGA2, and GGA3) have been identified in mammals. They may appear to behave similarly, since all of them have a multidomain structure consisting of: an N-terminal VHS (Vps27/Hrs/Stam) domain that binds the acidic-cluster dileucine (DxxLL)-type sorting signals (where x is any amino acid) found in the cytoplasmic tail of TGN sorting receptors; a GAT (GGA and TOM) domain that interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and the tumor susceptibility gene 101 product (TSG101); a largely unstructured hinge region that contains clathrin-binding motifs; and a C-terminal GAE (gamma-adaptin ear homology) domain that binds accessory proteins. However, the three GGAs have some differences, which suggest they may possess their own distinct roles. For instance, both GGA1 and GGA3, but not GGA2, contains an internal DxxLL motif that binds to it own VHS domain. Only a portion of the VHS domain of GGA2 possesses distant structural homology to that of GGA1 or GGA3. Moreover, the binding affinity of GGA2 to ubiquitin is quite lower than that of GGA1 or GGA3. In addition, GGA3 has a short splicing variant that is predominantly expressed in human cell lines and tissues except the brain. It does have a VHS domain, but it is unable to bind to the DxxLL motif. GGA2 and GGA3 undergo epidermal growth factor (EGF)-induced phosphorylation.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1007382088 204 KLHSELDMVKMNVRVMSAILMENTPGSENHEDIELLQKLYKTGREMQERIMDL-LVVVENEDVTVELIQVNEDLNNAILG 282
Cdd:cd14234     1 KRLLELEEVNNNVKLLNEMLDHYSPGESSQDELELMKELYESCEKMRPTLFRLaSETDDDDEGLADILQANDELTRVMQR 80

                  ...
gi 1007382088 283 YER 285
Cdd:cd14234    81 YKN 83