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        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568975927 164 QEIGKLHSELDMVKMNVKVMTAILMENTPGSENHEDIELLRKLYKTGREMQERIMDLLVVVENEDVTMELIQVNEDLNNA 243
Cdd:cd14237    2 EQIGKLYSELDIVKMNVRVMSAILLENTPGAENPEDMELLEKLYKTCREMQERIMKLLETVENEDVIIELIQVNDDLNNV 81

                         90
                 ....*....|.
gi 568975927 244 VLGYERFTRNQ 254
Cdd:cd14237   82 FLRHERFSRNR 92

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 568975927 164 QEIGKLHSELDMVKMNVKVMTAILMENTPGSENHEDIELLRKLYKTGREMQERIMDLLVVVENEDVTMELIQVNEDLNNA 243
Cdd:cd14237    2 EQIGKLYSELDIVKMNVRVMSAILLENTPGAENPEDMELLEKLYKTCREMQERIMKLLETVENEDVIIELIQVNDDLNNV 81

                         90
                 ....*....|.
gi 568975927 244 VLGYERFTRNQ 254
Cdd:cd14237   82 FLRHERFSRNR 92

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568975927   14 SVGHLIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRIsKNYNHKEIQLSLSLIDMCVQNCGPSFQSLIVK 93
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRI-NSPNPHVALLALTLLDACVKNCGSKFHLEIAS 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 568975927   94 KEFIkDTLVKLLNPRYTLPLET-QNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLKKG 150
Cdd:pfam00790  80 KEFL-NELVKLIPNKPYGKPAKvKKKILELIQEWADAFKNDPDLKYIRDMYKLLKRKG 136

VHS (Vps27/Hrs/STAM) domain of Tom1 subfamily; This subfamily is composed of Tom1 (Target of myb1 - retroviral oncogene) protein, Tom1L1 (Tom1-like1), Tom1L2 (Tom1-like2), and similar proteins. Proteins belonging to this subfamily are 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. Yeast do not contain homologous proteins of the Tom1 subfamily, suggesting these proteins have evolved to accommodate more complex cellular processes. Tom1 is essential for the negative regulation of Interleukin-1 and Tumor Necrosis Factor-induced signaling pathways. 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 568975927  14 SVGHLIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKN--YNHKEIQLSLSLIDMCVQNCGPSFQSLI 91
Cdd:cd03565    1 PVGQLIERATDSGLSSEDWALNMEICDMINETDDGPKDAIKAIKKRLSTNagKNHTVVMYTLTLLETCVKNCGHRFHVLV 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 568975927  92 VKKEFIKDtLVKLLNPRYTLPLETQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLKKG 150
Cdd:cd03565   81 ANKDFLQE-LVKLIGPKNDPPTIVQEKVLSLIQSWADAFRGQPDLQEVVKVYQELKAKG 138

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568975927    15 VGHLIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISkNYNHKEIQLSLSLIDMCVQNCGPSFQSLIVKK 94
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLINSTPDGPKDAVRLLKKRLN-NKNPHVALLALTLLDACVKNCGSKFHLEVASK 79

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 568975927    95 EFIkDTLVKLLNPRYTLPLeTQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLKKG 150
Cdd:smart00288  80 EFL-NELVKLIKPKYPLPL-VKKRILELIQEWADAFKNDPDLSQIVDVYDLLKKKG 133

VHS (Vps27/Hrs/STAM) domain of TOM1-like protein 2; TOM1-like protein 2 (Tom1L2) 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. Studies in Tom1L2 hypomorphic mice suggest that Tom1L2 may play roles in immune responses and tumor suppression. 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 568975927  15 VGHLIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQLSLSLIDMCVQNCGPSFQSLIVKK 94
Cdd:cd16996    2 VGQCIEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNKNYREVMLALTVLETCVKNCGHRFHVLVASR 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 568975927  95 EFIKDTLVKLLNPRYTLPLETQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLKKG 150
Cdd:cd16996   82 DFIDGVLVKIISPKNNPPTIVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 137

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 568975927  18 LIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRIsKNYNHKEIQLSLSLIDMCVQNCGPSFQSLIVKKEFI 97
Cdd:cd03561    4 LVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRL-QSKNPKVQLLALTLLETLVKNCGAPFHSEVASRDFL 82

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 568975927  98 kDTLVKLLNPRYTlPLETQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLK 148
Cdd:cd03561   83 -QELVKLVKKKKT-SPEVREKALALIQEWAEAFQGDGRLPLFYDTYQQLRR 131

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568975927   14 SVGHLIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRIsKNYNHKEIQLSLSLIDMCVQNCGPSFQSLIVK 93
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRI-NSPNPHVALLALTLLDACVKNCGSKFHLEIAS 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 568975927   94 KEFIkDTLVKLLNPRYTLPLET-QNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLKKG 150
Cdd:pfam00790  80 KEFL-NELVKLIPNKPYGKPAKvKKKILELIQEWADAFKNDPDLKYIRDMYKLLKRKG 136

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 568975927  18 LIEKATF----AGvlTEDWGQFLHICDIINTTQDGPKDAVKALKKRI-SKNYNhkeIQLS-LSLIDMCVQNCGPSFQSLI 91
Cdd:cd16979    6 LIEKATSesipNG--EEDLALALEISDLIRSKSVPPKDAMRSLKKRIlHKNPN---VQLLaLKLTDVCVKNGGDHFLVEI 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568975927  92 VKKEFIkDTLVKLLNPRYTLPlETQNRILNFIKTWSQGFPGGVDVSEVKEVYLDLLKKGVQFP 154
Cdd:cd16979   81 ASREFM-DNLVSLIRSTGVNP-EVKEKILRLIQEWALAFKSKSQLSYVVEVYKKLKSEGIEFP 141

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 568975927  19 IEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQlSLSLIDMCVQNCGPSFQSLIVKKEFIK 98
Cdd:cd16977    5 INRATNPSNAEPDWALILGFCDQINEDGEGPRDAARLLAHKIQSPQEWEAIQ-ALTVLEVCMKNCGYRFHLEVGKFRFLN 83

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 568975927  99 DtLVKLLNPRYTLPLET---QNRILNFIKTWSQGFPggvDVSEVKEVYlDLLKK 149
Cdd:cd16977   84 E-LIKVVSPKYLGSRRSekvKRKILELLYSWTVTLP---EEGKIRDAY-QMLKK 132

VHS (Vps27/Hrs/STAM) domain of the STAM (Signal Transducing Adaptor Molecule) subfamily; 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. Jawed vertebrates have two STAM subfamily members, STAM1 and STAM2.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568975927  18 LIEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRIsknyNHKE---IQLSLSLIDMCVQNCGPSFQSLIVKK 94
Cdd:cd03568    4 DVEKATSEKNTSENWSLILDICDKVGRSPNGAKDCLKSIMKRL----NHKDphvALQALTLLDACVKNCGKIFHLEVCSR 79

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 568975927  95 EFIKDtLVKLLNPRYTLPLEtqnRILNFIKTWSQGF 130
Cdd:cd03568   80 DFESE-LRKLLTKSHPKVAE---KLKELLKKWAEEE 111

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 568975927  19 IEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQlSLSLIDMCVQNCGPSFQSLIVKKEF-- 96
Cdd:cd16999    5 VEKATNEYNTSEDWSLIMDICDKVGSTPNGAKDCLKAIMKRVNHKVPHVALQ-ALTLLGACVSNCGKIFHLEVCSRDFat 83

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 568975927  97 -IKDTLVKLLNPRYTLPLETqnrilnFIKTWSQGFPGGVDVSEVKEVYLDLLKKGVQFPPS 156
Cdd:cd16999   84 eVRAVIKNKAHPKVCEKLKA------LMVEWSEEFQKDPQFSLISATIKSLKEEGITFPPA 138

VHS, ENTH and ANTH domain superfamily; This superfamily is composed of proteins containing a VHS, CID, ENTH, or ANTH domain. 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 is located at the N-termini of proteins involved in intracellular membrane trafficking. The CTD-Interacting Domain (CID) is present in several RNA-processing factors and binds tightly to the carboxy-terminal domain (CTD) of RNA polymerase II (RNAP II or Pol II). The epsin N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated endocytosis. A set of proteins previously designated as harboring an ENTH domain in fact contains a highly similar, yet unique module referred to as an AP180 N-Terminal Homology (ANTH) domain. VHS, ENTH, and ANTH domains are structurally similar and are composed of a superhelix of eight alpha helices. ENTH and ANTH (E/ANTH) domains bind both inositol phospholipids and proteins and contribute to the nucleation and formation of clathrin coats on membranes. ENTH domains also function in the development of membrane curvature through lipid remodeling during the formation of clathrin-coated vesicles. E/ANTH domain-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the Trans-Golgi Network, which suggests that E/ANTH domains are universal components of the machinery for clathrin-mediated membrane budding.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568975927  19 IEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKNyNHKEIQLSLSLIDMCVQNCGPSFQSLIVKKEFIK 98
Cdd:cd00197    5 VEKATSNENMGPDWPLIMEICDLINETNVGPKEAVDAIKKRINNK-NPHVVLKALTLLEYCVKNCGERFHQEVASNDFAV 83

                         90       100       110
                 ....*....|....*....|....*....|.
gi 568975927  99 DTLVKLLNPR--YTLPLETQNRILNFIKTWS 127
Cdd:cd00197   84 ELLKFDKSGLlgDDVSTNVREKAIELVQLWA 114

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 568975927  18 LIEKATFAGVLTEDWGQFLHICDIINTTQ-DGPKDAVKALKKRISkNYNHKEIQLSLSLIDMCVQNCGPSFQSLIVKKEF 96
Cdd:cd16998    4 YIERACDPSLEEPNLALNLEIADLINEKQgNTPREAAFAIVRLVN-SRNPTVALLALHLLDVCVKNCGYPFHLQIASKEF 82

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 568975927  97 IkDTLVKLL--NPRYTLPLeTQNRILNFIKTWSQG 129
Cdd:cd16998   83 L-NELVRRFpeRPPSRLNP-VQHKILELIEEWKQT 115

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 568975927  19 IEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQlSLSLIDMCVQNCGPSFQSLIVKKEFIK 98
Cdd:cd17009    6 INRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQ-ALTVLETCMKSCGKRFHDEVGKFRFLN 84

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 568975927  99 DtLVKLLNPRY---TLPLETQNRILNFIKTWSQGFPGGVDVSevkEVYLDLLKKGV 151
Cdd:cd17009   85 E-LIKVVSPKYlgsRTPEKVKNKILELLYSWTVGLPEEVKIA---EAYQMLKKQGI 136

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 568975927  19 IEKATFAGVLTEDWGQFLHICDIINTTQDGPKDAVKALKKRISKNYNHKEIQlSLSLIDMCVQNCGPSFQSLIVKKEF 96
Cdd:cd17000    5 VEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVNHKDPHVAMQ-ALTLLGACVSNCGKIFHLEVCSRDF 81

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 568975927 174 DMVKMNVKVMTAILMENTPGSENHEDIELLRKLYKTGREMQERIMDLLVVVENEDVTMELIQVNEDLNNAVLGYERF 250
Cdd:cd12930    1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLNDKADDQKYNTLLE*NDNLSEV*NIYDRL 77