canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins GGA1 and GGA2; This subfamily includes GGA1 and GGA2, both of which 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. GGA1, also called gamma-adaptin-related protein 1, or Golgi-localized gamma ear-containing Arf-binding protein 1, regulates the low-density lipoprotein and sorting receptor LR11/SorLA endocytic traffic and further alters amyloid-beta precursor protein (APP) intracellular distribution and amyloid-beta production. It is also critical for the effects of beta-site APP-cleaving enzyme-1 (BACE1) on amyloid-beta generation. It interacts with BACE1 and promotes its traffic from early endosomes to late endocytic compartments or the TGN. Moreover, GGA1 acts as a clathrin assembly protein with the ability to polymerize clathrin into tubules. GGA2, also called gamma-adaptin-related protein 2, Golgi-localized gamma ear-containing Arf-binding protein 2, or VHS domain and ear domain of gamma-adaptin (Vear), interacts with the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR) and further plays a major role in the sorting of lysosomal enzymes. It also mediates a vital function that cannot be compensated for by GGA1 and/or GGA3. Both GGA1 and GGA2 have 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541  227 KVSKRVSAVEEVRSHVKVLQEMLSMYRRPGQAPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQG 306
Cdd:cd14239   1 KVSKRVNAIEEVNNNVKLLTEMLMSYSRGELSESSEELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNLTQV 80

                ....*...
gi 7021541  307 VLLYKQVM 314
Cdd:cd14239  81 INLYKQLV 88

N-terminal extension of GAT domain; This region is found in the N-terminal region of the GGA and Tom1 (GAT) domain in Golgi-localizing gamma-adaptin ARF-binding protein 1 (GGA1) present in Homo sapiens. The GAT domain is the key region in GGA that interacts with ARF. ARF plays a crucial role in docking adaptor proteins to membranes. This region is referred to as N-GAT and it interacts extensively with ARF.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 7021541    185 FDaDEEKSKLLTRLLKSNHPEDLQAANRLIKNLVKEEQEK 224
Cdd:pfam18308   1 FD-DEEKSKLLARLLKSKNPEDLQAANRLIKSMVKEDDER 39

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541     25 SLELWLNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKF 104
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRINSPNPHVALLALTLLDACVKNCGSKFHLEIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 7021541    105 RFLNELIKVLSPKYLGSWAtgKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 159
Cdd:pfam00790  81 EFLNELVKLIPNKPYGKPA--KVKKKILELIQEWADAFkndPDLKYIRDMYKLLKRKG 136

canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins GGA1 and GGA2; This subfamily includes GGA1 and GGA2, both of which 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. GGA1, also called gamma-adaptin-related protein 1, or Golgi-localized gamma ear-containing Arf-binding protein 1, regulates the low-density lipoprotein and sorting receptor LR11/SorLA endocytic traffic and further alters amyloid-beta precursor protein (APP) intracellular distribution and amyloid-beta production. It is also critical for the effects of beta-site APP-cleaving enzyme-1 (BACE1) on amyloid-beta generation. It interacts with BACE1 and promotes its traffic from early endosomes to late endocytic compartments or the TGN. Moreover, GGA1 acts as a clathrin assembly protein with the ability to polymerize clathrin into tubules. GGA2, also called gamma-adaptin-related protein 2, Golgi-localized gamma ear-containing Arf-binding protein 2, or VHS domain and ear domain of gamma-adaptin (Vear), interacts with the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR) and further plays a major role in the sorting of lysosomal enzymes. It also mediates a vital function that cannot be compensated for by GGA1 and/or GGA3. Both GGA1 and GGA2 have 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541  227 KVSKRVSAVEEVRSHVKVLQEMLSMYRRPGQAPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQG 306
Cdd:cd14239   1 KVSKRVNAIEEVNNNVKLLTEMLMSYSRGELSESSEELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNLTQV 80

                ....*...
gi 7021541  307 VLLYKQVM 314
Cdd:cd14239  81 INLYKQLV 88

Adaptin C-terminal domain; Alpha adaptin is a heterotetramer which regulates clathrin-bud formation. The carboxyl-terminal appendage of the alpha subunit regulates translocation of endocytic accessory proteins to the bud site. This ig-fold domain is found in alpha, beta and gamma adaptins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541    487 PPLIVYDRNGFRILLHFSQTGapgHPEVQVLLLTMMSTAPQPVWDIMFQVAVPKSMRVKLQPASSSKLPAFsplmPPAVI 566
Cdd:pfam02883   1 PPVVLYESDGLQIGFSFERSR---RPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPN----PGGQI 73

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 7021541    567 SQMLLLDNPHKEPIRLRYKLTFNqGGQPFSEVGEVKDFP 605
Cdd:pfam02883  74 TQVLLIENPGKKPLRMRLKISYL-NGGAVQEQGDVLKFP 111

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 7021541    239 RSHVKVLQEMLSMYRRPGqaPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQGVLLYKQVMEG 316
Cdd:pfam03127   1 RNNAKLLNEMLSSTDPDE--ELDNELIKELYERCKSAQPKIQKLIEETSDEDDLLAELLQLNDDLNNVLERYERLKKG 76

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 7021541   25 SLELWLNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKF 104
Cdd:cd03567   1 SLEYLLNKATNPFNTEEDWEAIDAFCDRVNKEPEGPQIAVRLLAHKIQSPNEKEALRALTVLEACVKNCGPRFHSEVGKF 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 7021541  105 RFLNELIKVLSPKYLGSWATGKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGIIK 162
Cdd:cd03567  81 RFLNELIKLVSPKYLGNRTPEEVKQKIIELLYSWTRSLPHEPKIKEAYDMLKKQGIIK 138

VHS (Vps27/Hrs/STAM) domain of ADP-ribosylation factor-binding protein GGA3; ADP-ribosylation factor-binding protein GGA3 (Golgi-localized, Gamma-ear-containing, Arf-binding 3) regulates the trafficking and is required for the lysosomal degradation of BACE (beta-site APP-cleaving enzyme), the protease that initiates the production of beta-amyloid, which causes Alzheimer's disease. It also plays a key role in GABA (+) transmission, which is important in the regulation of anxiety-like behaviors. GGA3 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 7021541   25 SLELWLNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKF 104
Cdd:cd17008   3 SLESWLNKATNPSNRQEDWEYIIGFCDQINKELEGPQIAVRLLAHKIQSPQEWEALQALTVLEACMKNCGRRFHNEVGKF 82

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*..
gi 7021541  105 RFLNELIKVLSPKYLGSWATGKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGII 161
Cdd:cd17008  83 RFLNELIKVVSPKYLGDRVSEKVKTKVIELLYSWTVALPEEAKIKDAYHMLKRQGIV 139

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541     25 SLELWLNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKF 104
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRINSPNPHVALLALTLLDACVKNCGSKFHLEIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 7021541    105 RFLNELIKVLSPKYLGSWAtgKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 159
Cdd:pfam00790  81 EFLNELVKLIPNKPYGKPA--KVKKKILELIQEWADAFkndPDLKYIRDMYKLLKRKG 136

canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins GGA1 and GGA2; This subfamily includes GGA1 and GGA2, both of which 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. GGA1, also called gamma-adaptin-related protein 1, or Golgi-localized gamma ear-containing Arf-binding protein 1, regulates the low-density lipoprotein and sorting receptor LR11/SorLA endocytic traffic and further alters amyloid-beta precursor protein (APP) intracellular distribution and amyloid-beta production. It is also critical for the effects of beta-site APP-cleaving enzyme-1 (BACE1) on amyloid-beta generation. It interacts with BACE1 and promotes its traffic from early endosomes to late endocytic compartments or the TGN. Moreover, GGA1 acts as a clathrin assembly protein with the ability to polymerize clathrin into tubules. GGA2, also called gamma-adaptin-related protein 2, Golgi-localized gamma ear-containing Arf-binding protein 2, or VHS domain and ear domain of gamma-adaptin (Vear), interacts with the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR) and further plays a major role in the sorting of lysosomal enzymes. It also mediates a vital function that cannot be compensated for by GGA1 and/or GGA3. Both GGA1 and GGA2 have 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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541  227 KVSKRVSAVEEVRSHVKVLQEMLSMYRRPGQAPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQG 306
Cdd:cd14239   1 KVSKRVNAIEEVNNNVKLLTEMLMSYSRGELSESSEELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNLTQV 80

                ....*...
gi 7021541  307 VLLYKQVM 314
Cdd:cd14239  81 INLYKQLV 88

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 7021541   26 LELWLNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKFR 105
Cdd:cd03561   1 VEELVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRLQSKNPKVQLLALTLLETLVKNCGAPFHSEVASRD 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 7021541  106 FLNELIKVLSPKYLGSwatgKVKGRVIEILFSWTVWFPEDIK---IRDAYQMLKK 157
Cdd:cd03561  81 FLQELVKLVKKKKTSP----EVREKALALIQEWAEAFQGDGRlplFYDTYQQLRR 131

Adaptin C-terminal domain; Alpha adaptin is a heterotetramer which regulates clathrin-bud formation. The carboxyl-terminal appendage of the alpha subunit regulates translocation of endocytic accessory proteins to the bud site. This ig-fold domain is found in alpha, beta and gamma adaptins.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 7021541    487 PPLIVYDRNGFRILLHFSQTGapgHPEVQVLLLTMMSTAPQPVWDIMFQVAVPKSMRVKLQPASSSKLPAFsplmPPAVI 566
Cdd:pfam02883   1 PPVVLYESDGLQIGFSFERSR---RPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPN----PGGQI 73

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 7021541    567 SQMLLLDNPHKEPIRLRYKLTFNqGGQPFSEVGEVKDFP 605
Cdd:pfam02883  74 TQVLLIENPGKKPLRMRLKISYL-NGGAVQEQGDVLKFP 111

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 7021541   32 KATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEK---EALYALTVLEMCMNHCGEKFHSEVAKFRFLN 108
Cdd:cd03565   8 RATDSGLSSEDWALNMEICDMINETDDGPKDAIKAIKKRLSTNAGKnhtVVMYTLTLLETCVKNCGHRFHVLVANKDFLQ 87

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....
gi 7021541  109 ELIKVLSPKYLGSWAtgkVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 159
Cdd:cd03565  88 ELVKLIGPKNDPPTI---VQEKVLSLIQSWADAFrgqPDLQEVVKVYQELKAKG 138

N-terminal extension of GAT domain; This region is found in the N-terminal region of the GGA and Tom1 (GAT) domain in Golgi-localizing gamma-adaptin ARF-binding protein 1 (GGA1) present in Homo sapiens. The GAT domain is the key region in GGA that interacts with ARF. ARF plays a crucial role in docking adaptor proteins to membranes. This region is referred to as N-GAT and it interacts extensively with ARF.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 7021541    185 FDaDEEKSKLLTRLLKSNHPEDLQAANRLIKNLVKEEQEK 224
Cdd:pfam18308   1 FD-DEEKSKLLARLLKSKNPEDLQAANRLIKSMVKEDDER 39

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 7021541    239 RSHVKVLQEMLSMYRRPGqaPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQGVLLYKQVMEG 316
Cdd:pfam03127   1 RNNAKLLNEMLSSTDPDE--ELDNELIKELYERCKSAQPKIQKLIEETSDEDDLLAELLQLNDDLNNVLERYERLKKG 76

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 7021541   30 LNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQE-KEALYALTVLEMCMNHCGEKFHSEVAKFRFLN 108
Cdd:cd16996   6 IEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNKNyREVMLALTVLETCVKNCGHRFHVLVASRDFID 85

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 7021541  109 E-LIKVLSPKylgSWATGKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 159
Cdd:cd16996  86 GvLVKIISPK---NNPPTIVQDKVLALIQAWADAFrssPDLTGVVHIYEELKRKG 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 7021541   30 LNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKI-QSPQEKEALYALTVLEMCMNHCGEKFHSEVAKFRFLN 108
Cdd:cd16997   6 IEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRIsKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVKKEFVK 85

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 7021541  109 E-LIKVLSPKYLgswATGKVKGRVIEILFSWTVWFPEDI---KIRDAYQMLKKQG 159
Cdd:cd16997  86 DvLVKLLNPRYN---LPVDLQNKILNFIMTWAQGFQGGVdvsEVKEVYLDLVKKG 137

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 7021541   31 NKATDPSMSEQDWSAIQNFCEQVNTDP-NGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKFRFLNE 109
Cdd:cd16978   6 IKATDETLTSENWQYILDVCDKVNSDPeDGAREAIAAIQKRLQHRNANVQLRSLSLADALAKNCGSRLHQEISSRSFTQT 85

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
gi 7021541  110 LIKVLSPKYLGSwatgKVKGRVIEILFSWTVWFPEDIK---IRDAYQMLKKQG 159
Cdd:cd16978  86 LLRLINDRTTHA----TVKKRILELIKQLSDSFKSDPSlglMSDTYDQLKSKY 134

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 7021541   26 LELWLNKATDPSMSEQDWSAIQNFCEQVN-TDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKF 104
Cdd:cd16998   1 LQRYIERACDPSLEEPNLALNLEIADLINeKQGNTPREAAFAIVRLVNSRNPTVALLALHLLDVCVKNCGYPFHLQIASK 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 7021541  105 RFLNELIKVL---SPKYLgswatGKVKGRVIEILFSWTV------WFPEDIK-IRDAYQMLK 156
Cdd:cd16998  81 EFLNELVRRFperPPSRL-----NPVQHKILELIEEWKQtlcktsRYKEDLGhIRDMHRLLS 137

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 7021541   30 LNKATDPSMSEQDWSAIQNFCEQVNTDPNGPTHAPWLLAHKIQSPQEKEALYALTVLEMCMNHCGEKFHSEVAKFRFLNE 109
Cdd:cd17000   5 VEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVNHKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDFASE 84

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*..
gi 7021541  110 LIKVLSPKYlgswatGKVKGRVIEILFSWTVWFPEDIKIRDAYQMLK 156
Cdd:cd17000  85 VSNVLNKGH------PKVCEKLKALMVEWTEEFKNDPQLSLISAMIK 125

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 7021541  236 EEVRSHVKVLQEMLSMYRRPGQAPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDaLAEILQANDLLTQGVLLYKQV 313
Cdd:cd12930   1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLNDKADDQK-YNTLLE*NDNLSEV*NIYDRL 77

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 7021541   80 LYALTVLEMCMNHCGEKFHSEVAKFRFLNELIKVLspkyLGSWATGKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLK 156
Cdd:cd16979  59 LLALKLTDVCVKNGGDHFLVEIASREFMDNLVSLI----RSTGVNPEVKEKILRLIQEWALAFkskSQLSYVVEVYKKLK 134

                ....*
gi 7021541  157 KQGII 161
Cdd:cd16979 135 SEGIE 139

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 7021541  229 SKRVSA-VEEVRSHVKVLQEMLSMyRRPGQAPPDQEALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQGV 307
Cdd:cd14235   3 KAQVAEeLEKLKRKAILLNEMLNN-ATPGEIDVEGDTYDELASSLKSAQPKIQKIIEEESEDEESVQKLLELNDLINSLL 81

                        90
                ....*....|.
gi 7021541  308 LLYKQVMEGRV 318
Cdd:cd14235  82 ERYDLLKKGDA 92