canonical GAT domain found in target of Myb-like protein 2 (Tom1L2); Tom1L2, together with Myb protein 1 (Tom1) and target of Myb-like protein 1 (Tom1L1), constitute the Tom1 family. Tom1L2 can interact with Toll-interacting protein (Tollip), clathrin, and ubiquitin. It may play a potential role in endosomal sorting, as well as in the regulation of membrane trafficking that is linked to immunity and cell proliferation. Tom1L2 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 564372312 218 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNN 297
Cdd:cd14238    1 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDPSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNN 80

                         90
                 ....*....|..
gi 564372312 298 VFLRYERFERYR 309
Cdd:cd14238   81 VFLRYERFERYR 92

canonical GAT domain found in target of Myb-like protein 2 (Tom1L2); Tom1L2, together with Myb protein 1 (Tom1) and target of Myb-like protein 1 (Tom1L1), constitute the Tom1 family. Tom1L2 can interact with Toll-interacting protein (Tollip), clathrin, and ubiquitin. It may play a potential role in endosomal sorting, as well as in the regulation of membrane trafficking that is linked to immunity and cell proliferation. Tom1L2 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 564372312 218 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNN 297
Cdd:cd14238    1 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDPSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNN 80

                         90
                 ....*....|..
gi 564372312 298 VFLRYERFERYR 309
Cdd:cd14238   81 VFLRYERFERYR 92

VHS domain; Domain present in VPS-27, Hrs and STAM.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312   12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVAN 91
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRIN-SPNPHVALLALTLLDACVKNCGSKFHLEIAS 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 564372312   92 RDFIDSVLVRIISPKNNPPTIVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 148
Cdd:pfam00790  80 KEFLNELVKLIPNKPYGKPAKVKKKILELIQEWADAFKNDPDLKYIRDMYKLLKRKG 136

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 564372312  12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSGNRNYREVMLALTVLETCVKNCGHRFHLLVAN 91
Cdd:cd16995    1 PVGQRIEKATDGSLQSEDWGLNMEICDIINETEEGPKDAIRAIKKRIVGNKNFREVMLALTVLETCVKNCGHRFHVLVAS 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*..
gi 564372312  92 RDFIDSVLVRIISPKNNPPTIVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 148
Cdd:cd16995   81 QDFVEGVLVKTILPKNNPPAIVHDKVLNLIQAWADAFRSSPDLTGVVTVYEDLRRKG 137

canonical GAT domain found in target of Myb-like protein 2 (Tom1L2); Tom1L2, together with Myb protein 1 (Tom1) and target of Myb-like protein 1 (Tom1L1), constitute the Tom1 family. Tom1L2 can interact with Toll-interacting protein (Tollip), clathrin, and ubiquitin. It may play a potential role in endosomal sorting, as well as in the regulation of membrane trafficking that is linked to immunity and cell proliferation. Tom1L2 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 564372312 218 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNN 297
Cdd:cd14238    1 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDPSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNN 80

                         90
                 ....*....|..
gi 564372312 298 VFLRYERFERYR 309
Cdd:cd14238   81 VFLRYERFERYR 92

VHS domain; Domain present in VPS-27, Hrs and STAM.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312   12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVAN 91
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRIN-SPNPHVALLALTLLDACVKNCGSKFHLEIAS 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 564372312   92 RDFIDSVLVRIISPKNNPPTIVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 148
Cdd:pfam00790  80 KEFLNELVKLIPNKPYGKPAKVKKKILELIQEWADAFKNDPDLKYIRDMYKLLKRKG 136

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 564372312  13 VGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLsGNRNYREVMLALTVLETCVKNCGHRFHLLVANR 92
Cdd:cd03561    1 VEELVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRL-QSKNPKVQLLALTLLETLVKNCGAPFHSEVASR 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 564372312  93 DFIDSvLVRIISPKNNPPTiVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKR 146
Cdd:cd03561   80 DFLQE-LVKLVKKKKTSPE-VREKALALIQEWAEAFQGDGRLPLFYDTYQQLRR 131

canonical GAT domain found in target of Myb protein 1 (Tom1); Tom1 was originally identified by its induced expression by the v-Myb oncogene. It is predominantly present in the cytosol and can interact with clathrin, endofin, Toll-interacting protein (Tollip), and ubiquitinated proteins. It acts as a linker protein to regulate the ability of endofin to recruit clathrin onto the sorting endosome. Moreover, Tom1 functions as a negative regulator of IL-1beta and tumor necrosis factor (TNF)-alpha-induced signaling pathways. It also plays a role in the TLR2/4 signaling pathways. Tom1 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). In contrast to GGAs, Tom1 binds to ubiquitin, ubiquitinated proteins, and Tollip through its GAT domain, but does not associate with Arf GTPases through its GAT domain nor with acidic cluster-dileucine sequences through its VHS domain. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312 218 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNN 297
Cdd:cd14236    1 PEQIGKLRSELEMVSGNVRVMSEMLTELVPTQAEPADLELLQELNRTCRAMQQRVLELIPQIANEQLTEELLIVNDNLNN 80

                         90
                 ....*....|....*
gi 564372312 298 VFLRYERFERYRSGR 312
Cdd:cd14236   81 VFLRHERFERFRTGQ 95

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 564372312  16 CLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFI 95
Cdd:cd03569    6 LLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLN-DQNPHVALYALQVLESVVKNCGTPVHDEVATKEFM 84

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 564372312  96 DSV--LVriispKNNPPTIVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKGIEFP 152
Cdd:cd03569   85 EELrdLV-----KTTTSENVRNKILELIQAWAHAFRNEPKYKIVQDTYNIMKMEGYKFP 138

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 564372312 219 EQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNNV 298
Cdd:cd14237    2 EQIGKLYSELDIVKMNVRVMSAILLENTPGAENPEDMELLEKLYKTCREMQERIMKLLETVENEDVIIELIQVNDDLNNV 81

                         90
                 ....*....|.
gi 564372312 299 FLRYERFERYR 309
Cdd:cd14237   82 FLRHERFSRNR 92

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 564372312  19 KATDGSLQSEDWTLNMEICDIINET-EEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDS 97
Cdd:cd16978    7 KATDETLTSENWQYILDVCDKVNSDpEDGAREAIAAIQKRLQ-HRNANVQLRSLSLADALAKNCGSRLHQEISSRSFTQT 85

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 564372312  98 VLVRIISPKNNppTIVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 148
Cdd:cd16978   86 LLRLINDRTTH--ATVKKRILELIKQLSDSFKSDPSLGLMSDTYDQLKSKY 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 564372312  15 QCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDF 94
Cdd:cd16999    3 QDVEKATNEYNTSEDWSLIMDICDKVGSTPNGAKDCLKAIMKRVN-HKVPHVALQALTLLGACVSNCGKIFHLEVCSRDF 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312  95 IDSVLvRIISPKNNPPtiVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKGIEFPMA 154
Cdd:cd16999   82 ATEVR-AVIKNKAHPK--VCEKLKALMVEWSEEFQKDPQFSLISATIKSLKEEGITFPPA 138

VHS (Vps27/Hrs/STAM) domain of GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) subfamily; 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. 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 564372312  17 LEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFID 96
Cdd:cd16977    5 INRATNPSNAEPDWALILGFCDQINEDGEGPRDAARLLAHKIQ-SPQEWEAIQALTVLEVCMKNCGYRFHLEVGKFRFLN 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 564372312  97 SvLVRIISPKnnPP-----TIVQDKVLALIQAWADAFrssPDLTGVVHIYEELKRK 147
Cdd:cd16977   84 E-LIKVVSPK--YLgsrrsEKVKRKILELLYSWTVTL---PEEGKIRDAYQMLKKQ 133

VHS (Vps27/Hrs/STAM) domain of fungal 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. Yeast GGAs facilitate the specific and direct delivery of vacuolar sorting receptor Vps10p and the processing protease Kex2p from the TGN to the late endosome/prevacuolar compartment (PVC). 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 564372312  17 LEKATDGSLQSEDWTLNMEICDIINETE-EGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFI 95
Cdd:cd16998    5 IERACDPSLEEPNLALNLEIADLINEKQgNTPREAAFAIVRLVN-SRNPTVALLALHLLDVCVKNCGYPFHLQIASKEFL 83

                         90       100       110
                 ....*....|....*....|....*....|..
gi 564372312  96 DSvLVRIIsPkNNPPTI---VQDKVLALIQAW 124
Cdd:cd16998   84 NE-LVRRF-P-ERPPSRlnpVQHKILELIEEW 112

VHS (Vps27/Hrs/STAM) domain of Signal Transducing Adapter Molecule 1; Signal Transducing Adapter Molecule 1 (STAM1) is part of a crucial regulatory axis for the ventral axonal trajectory of developing spinal motor neurons. It forms a complex with beta-arrestin, which regulates lysosomal trafficking of the chemokine receptor CXCR4 and also mediates CXCR4-dependent chemotaxis. 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 564372312  15 QCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDF 94
Cdd:cd17000    3 QDVEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVN-HKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDF 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 564372312  95 IDSvlVRIISPKNNPPtiVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 148
Cdd:cd17000   82 ASE--VSNVLNKGHPK--VCEKLKALMVEWTEEFKNDPQLSLISAMIKNLKEQG 131

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 564372312 229 DIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNNVFLRYERF 305
Cdd:cd12930    1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLNDKADDQKYNTLLE*NDNLSEV*NIYDRL 77

canonical GAT domain found in eukaryotic ADP-ribosylation factor (Arf)-binding proteins (GGAs), metazoan myb protein 1 (Tom1)-like proteins, and similar proteins; This model represents the canonical GAT (GGA and Tom1) domain found in GGAs from eukaryotes, 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. In addition, Tom1 family proteins recruit clathrin onto endosomes through their C-terminal region. The C-terminal clathrin-binding region of Tom1 and Tom1L2 are similar to each other, but distinguishable from Tom1L1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312 227 ELDIVRGNTKVMSEMLTEmvPGQEDSSDLELLQELNRTCRAMQHRIVELISRVS---NEEVTEELLHVNDDLNNVFLRYE 303
Cdd:cd21383    1 DLEEVKENASLLNEMLSA--ASPEELLDNELLQELVEFCRACQPRIVELIEATTdglDEDTLEELLELNDELNEALQRYD 78

                 ..
gi 564372312 304 RF 305
Cdd:cd21383   79 DL 80

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312 223 RLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVS-NEEVTEELLHVNDDLNNVFLR 301
Cdd:cd14234    1 KRLLELEEVNNNVKLLNEMLDHYSPGESSQDELELMKELYESCEKMRPTLFRLASETDdDDEGLADILQANDELTRVMQR 80

                 ...
gi 564372312 302 YER 304
Cdd:cd14234   81 YKN 83

canonical GAT domain found in fungal 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. Two GGAs (Gga1p and Gga2p) have been identified in the budding yeast Saccharomyces cerevisiae. Yeast GGAs play important roles in the carboxypeptidase Y (CPY) pathway, vacuole biogenesis, alpha-factor maturation, and interactions with clathrin. They have a multidomain structure consisting of VHS (Vps27/Hrs/ STAM), GAT (GGA and TOM), hinge, and GAE (gamma-adaptin ear) domains. Both Gga1p and Gga2p function as effectors of Arf in yeast. They interact with Arf1p and Arf2p in a GTP-dependent manner. Moreover, Gga2p mediates sequential ubiquitin-independent and ubiquitin-dependent steps in the trafficking of ARN1, a ferrichrome transporter in S. cerevisiae, from the TGN to the vacuole. It also acts as a phosphatidylinositol 4-phosphate effector at the Golgi exit, which binds directly to the TGN PtdIns(4)-kinase Pik1p and contributes to Pik1p recruitment. In addition, Gga2p is required for sorting of the yeast siderophore iron transporter1 (Sit1) to the vacuolar pathway. The GAT domain of GGAs interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and/or the tumor susceptibility gene 101 product (TSG101).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 564372312 222 ARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDlELLQELNRTCRAMQHRIVELISRVSN-EEVTEELLHVNDDLNNVFL 300
Cdd:cd14235    4 AQVAEELEKLKRKAILLNEMLNNATPGEIDVEG-DTYDELASSLKSAQPKIQKIIEEESEdEESVQKLLELNDLINSLLE 82

                 ...
gi 564372312 301 RYE 303
Cdd:cd14235   83 RYD 85

canonical GAT domain found in ADP-ribosylation factor-binding protein GGA3; GGA3, also called Golgi-localized gamma ear-containing Arf-binding protein 3, belongs 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. GGA3 interacts selectively with the Met/Hepatocyte Growth Factor receptor tyrosine kinase (RTK) when stimulated. It functions as a specific cargo adaptor to target the Met RTK into recycling tubules, and further coordinates the recycling, signaling and degradative fates of the Met RTK. Moreover, GGA3, together with PACS-1 and the protein kinase CK2, forms a complex that regulates cation-independent mannose-6-phosphate receptor (CI-MPR) trafficking. Furthermore, GGA3 has been identified as an interacting protein of the beta-site APP-cleaving enzyme-1 (BACE1), a stress-related protease that is involved in Alzheimer's disease (AD) pathology. GGA3 has a multidomain structure consisting of an N-terminal VHS (Vps27/Hrs/Stam) domain, a GAT (GGA and TOM) domain, a largely unstructured hinge region that contains clathrin-binding motifs, and a C-terminal GAE (gamma-adaptin ear homology) domain. The GAT domain of GGAs interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and/or the tumor susceptibility gene 101 product (TSG101).

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 564372312 228 LDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVS-NEEVTEELLHVNDDLNNVFLRYER 304
Cdd:cd14240    6 LEEVNNNVRLLNEMLAHYSKEDSSDGDKELMKELYDRCEKKRRTLFKLASETEdNDNSLGDILQASDDLSRVINSYKK 83

ENTH domain; The ENTH (Epsin N-terminal homology) domain is found in proteins involved in endocytosis and cytoskeletal machinery. The function of the ENTH domain is unknown.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 564372312   10 STPVGQCLEKATDgslqSEDW----TLNMEICDIINETEEGPkDAIRALKKRLSG-NRNYREVMLALTVLETCVKN 80
Cdd:pfam01417   1 YSETELKVREATN----NDPWgpsgTLMDEIARLTYNYVEFP-EIMKMLWKRLNDkGKNWRHIYKALTLLEYLLKN 71