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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388   9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:cd17010     2 LESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKFR 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2113270388  89 FLNELIKVLSPKYLGTWSTEKVKSRVIEIMFSWTVWFPQEVKIRDAYQMLKKQGVIKQ 146
Cdd:cd17010    82 FLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIKQ 139

Adaptin C-terminal domain; Adaptins are components of the adaptor complexes which link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. Gamma-adaptin is a subunit of the golgi adaptor. Alpha adaptin is a heterotetramer that 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 and consists of a beta-sandwich containing 7 strands in 2 beta-sheets in a greek-key topology.. The adaptor appendage contains an additional N-terminal strand.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388  506 VYDKDGFKVMIHFSRdlapgRPDVLVMVLSMLSTSTQPIKDIVFQAAVPKVMRVKLQPASGSELPAFSPllppavISQVL 585
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 2113270388  586 LLANPHRDPIRLRYKLMFTQGGRPFSEVGEVTGFP 620
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388   9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:cd17010     2 LESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKFR 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2113270388  89 FLNELIKVLSPKYLGTWSTEKVKSRVIEIMFSWTVWFPQEVKIRDAYQMLKKQGVIKQ 146
Cdd:cd17010    82 FLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIKQ 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388    9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLINSTPDGPKDAVRLLKKRLNNKNPHVALLALTLLDACVKNCGSKFHLEVASKE 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2113270388   89 FLNELIKVLSPKYLGtwstEKVKSRVIEIMFSWTVWFPQEVK---IRDAYQMLKKQG 142
Cdd:smart00288  81 FLNELVKLIKPKYPL----PLVKKRILELIQEWADAFKNDPDlsqIVDVYDLLKKKG 133

Adaptin C-terminal domain; Adaptins are components of the adaptor complexes which link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. Gamma-adaptin is a subunit of the golgi adaptor. Alpha adaptin is a heterotetramer that 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 and consists of a beta-sandwich containing 7 strands in 2 beta-sheets in a greek-key topology.. The adaptor appendage contains an additional N-terminal strand.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388  506 VYDKDGFKVMIHFSRdlapgRPDVLVMVLSMLSTSTQPIKDIVFQAAVPKVMRVKLQPASGSELPAFSPllppavISQVL 585
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 2113270388  586 LLANPHRDPIRLRYKLMFTQGGRPFSEVGEVTGFP 620
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

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 2113270388 223 SSVKLLGEMLTSYKRQELSTSDLqiLQSLFERCEKLRALLFRLASETTDDDEALAEILQANDKLTQALGLYRQVV 297
Cdd:pfam03127   2 NNAKLLNEMLSSTDPDEELDNEL--IKELYERCKSAQPKIQKLIEETSDEDDLLAELLQLNDDLNNVLERYERLK 74

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388   9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:cd17010     2 LESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKFR 81

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 2113270388  89 FLNELIKVLSPKYLGTWSTEKVKSRVIEIMFSWTVWFPQEVKIRDAYQMLKKQGVIKQ 146
Cdd:cd17010    82 FLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIKQ 139

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 2113270388   9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:cd16977     1 LERWINRATNPSNAEPDWALILGFCDQINEDGEGPRDAARLLAHKIQSPQEWEAIQALTVLEVCMKNCGYRFHLEVGKFR 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2113270388  89 FLNELIKVLSPKYLGTWSTEKVKSRVIEIMFSWTVWFPQEVKIRDAYQMLKKQ 141
Cdd:cd16977    81 FLNELIKVVSPKYLGSRRSEKVKRKILELLYSWTVTLPEEGKIRDAYQMLKKQ 133

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 2113270388   8 ALERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKF 87
Cdd:cd17009     1 TLEARINRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 2113270388  88 RFLNELIKVLSPKYLGTWSTEKVKSRVIEIMFSWTVWFPQEVKIRDAYQMLKKQGVIKQ 146
Cdd:cd17009    81 RFLNELIKVVSPKYLGSRTPEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2113270388    9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLINSTPDGPKDAVRLLKKRLNNKNPHVALLALTLLDACVKNCGSKFHLEVASKE 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 2113270388   89 FLNELIKVLSPKYLGtwstEKVKSRVIEIMFSWTVWFPQEVK---IRDAYQMLKKQG 142
Cdd:smart00288  81 FLNELVKLIKPKYPL----PLVKKRILELIQEWADAFKNDPDlsqIVDVYDLLKKKG 133

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 2113270388   9 LERWLHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFR 88
Cdd:cd00197     1 FEKTVEKATSNENMGPDWPLIMEICDLINETNVGPKEAVDAIKKRINNKNPHVVLKALTLLEYCVKNCGERFHQEVASND 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 2113270388  89 FLNELIKVLSPKYLGTWSTEKVKSRVIEIMFSWT 122
Cdd:cd00197    81 FAVELLKFDKSGLLGDDVSTNVREKAIELVQLWA 114

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 2113270388 213 KRLNAIDEVHSSVKLLGEMLTSYKRQELSTSDLQILQSLFERCEKLRALLFRLASETTDDDEALAEILQANDKLTQALGL 292
Cdd:cd14234     1 KRLLELEEVNNNVKLLNEMLDHYSPGESSQDELELMKELYESCEKMRPTLFRLASETDDDDEGLADILQANDELTRVMQR 80

                  ....
gi 2113270388 293 YRQV 296
Cdd:cd14234    81 YKNL 84

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 2113270388 502 PPVTVYDKDGFKVMIHFSRDlapGRPDVLVMVLSMLSTSTQPIKDIVFQAAVPKVMRVKLQPASGSELPAFspllPPAVI 581
Cdd:pfam02883   1 PPVVLYESDGLQIGFSFERS---RRPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPN----PGGQI 73

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 2113270388 582 SQVLLLANPHRDPIRLRYKLMFTQGGrPFSEVGEVTGFP 620
Cdd:pfam02883  74 TQVLLIENPGKKPLRMRLKISYLNGG-AVQEQGDVLKFP 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 2113270388  15 KATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQ---EMEALHALTVLETCVNNCGERFHNEVAKFRFLN 91
Cdd:cd03565     8 RATDSGLSSEDWALNMEICDMINETDDGPKDAIKAIKKRLSTNAgknHTVVMYTLTLLETCVKNCGHRFHVLVANKDFLQ 87

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 2113270388  92 ELIKVLSPKYLgtwSTEKVKSRVIEIMFSWTVWFPQEVKIRD---AYQMLKKQG 142
Cdd:cd03565    88 ELVKLIGPKND---PPTIVQEKVLSLIQSWADAFRGQPDLQEvvkVYQELKAKG 138

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 2113270388  15 KATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFRFLNELI 94
Cdd:cd03568     7 KATSEKNTSENWSLILDICDKVGRSPNGAKDCLKSIMKRLNHKDPHVALQALTLLDACVKNCGKIFHLEVCSRDFESELR 86

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 2113270388  95 KVLSPkylgtwSTEKVKSRVIEIMFSWTVWF----PQEVKIRDAYQMLKKQG 142
Cdd:cd03568    87 KLLTK------SHPKVAEKLKELLKKWAEEEfkddPQLSLIPSLYKKLKAEG 132

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 2113270388  13 LHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEM-EALHALTVLETCVNNCGERFHNEVAKFRFLN 91
Cdd:cd16996     6 IEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNKNYrEVMLALTVLETCVKNCGHRFHVLVASRDFID 85

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2113270388  92 E-LIKVLSPKylgTWSTEKVKSRVIEIMFSWTVWF---PQEVKIRDAYQMLKKQG 142
Cdd:cd16996    86 GvLVKIISPK---NNPPTIVQDKVLALIQAWADAFrssPDLTGVVHIYEELKRKG 137

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 2113270388 168 FDvDDEKSKLLARLLKSNHPEDLQAANRLIKSMIKEEQEK 207
Cdd:pfam18308   1 FD-DEEKSKLLARLLKSKNPEDLQAANRLIKSMVKEDDER 39

canonical GAT domain found in metazoan and 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. GGAs also play important roles in ubiquitin-dependent sorting of cargo proteins both in biosynthetic and endocytic pathways. The family includes three GGAs (GGA1, GGA2, and GGA3) identified in mammals and two GGAs (Gga1p and Gga2p) identified in the budding yeast Saccharomyces cerevisiae. All these GGAs have a multidomain structure consisting of: an N-terminal VHS (Vps27/Hrs/Stam) domain that binds 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. In contrast to other GGAs-like proteins, members of this family contain a GAT N-terminal region, a helix-loop-helix in the complex with Arf1-GTP.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2113270388 218 IDEVHSSVKLLGEMLTSYKRQELSTSDLQILQSLFERCEKLRALLFRLASETTDDDEALAEILQANDKLTQALGLYR 294
Cdd:cd14230     2 LEEAKNNVDLLDEMLLSYSQEDSSDGDNELMKELYDQLENMRPTLFKLASETEENDNSLGDVLQASDNVNRVINKYK 78

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 2113270388  13 LHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKI-QSPQEMEALHALTVLETCVNNCGERFHNEVAKFRFLN 91
Cdd:cd16997     6 IEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRIsKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVKKEFVK 85

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 2113270388  92 E-LIKVLSPKYLGTWStekVKSRVIEIMFSWTVWFPQEV---KIRDAYQMLKKQG 142
Cdd:cd16997    86 DvLVKLLNPRYNLPVD---LQNKILNFIMTWAQGFQGGVdvsEVKEVYLDLVKKG 137

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 2113270388 219 DEVHSSVKLLGEMLTSYKRQELSTSDLQILQSLFERCEKLRALLFRLASEtTDDDEALAEILQANDKLTQALGLYRQV 296
Cdd:cd12930     1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLND-KADDQKYNTLLE*NDNLSEV*NIYDRL 77

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 2113270388  13 LHKATDPSIPEENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVAKFRFLNE 92
Cdd:cd17000     5 VEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVNHKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDFASE 84

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2113270388  93 LIKVLSPKYlgtwstEKVKSRVIEIMFSWTVWF---PQEVKIRDAYQMLKKQG 142
Cdd:cd17000    85 VSNVLNKGH------PKVCEKLKALMVEWTEEFkndPQLSLISAMIKNLKEQG 131

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 2113270388   8 ALERWLHKATDPSIP--EENWECIQRFCDQVNADPEGPSIAPRLLAHKIQSPQEMEALHALTVLETCVNNCGERFHNEVA 85
Cdd:cd16979     2 EFDELIEKATSESIPngEEDLALALEISDLIRSKSVPPKDAMRSLKKRILHKNPNVQLLALKLTDVCVKNGGDHFLVEIA 81

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2113270388  86 KFRFLNELIKVLspkyLGTWSTEKVKSRVIEIMFSWTVWF---PQEVKIRDAYQMLKKQGVI 144
Cdd:cd16979    82 SREFMDNLVSLI----RSTGVNPEVKEKILRLIQEWALAFkskSQLSYVVEVYKKLKSEGIE 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 2113270388 208 SAKVSKRLnaiDEVHSSVKLLGEMLTSYKRQELSTSDlQILQSLFERCEKLRALLFRLASETTDDDEALAEILQANDKLT 287
Cdd:cd14235     3 KAQVAEEL---EKLKRKAILLNEMLNNATPGEIDVEG-DTYDELASSLKSAQPKIQKIIEEESEDEESVQKLLELNDLIN 78

                          90
                  ....*....|...
gi 2113270388 288 QALGLYRQVVVGH 300
Cdd:cd14235    79 SLLERYDLLKKGD 91

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 2113270388 219 DEVHSSVKLLGEMLTSYKRQELSTSDLQILQSLFERC----EKLRALLFRLasettDDDEALAEILQANDKLTQA 289
Cdd:cd14233     9 DVVEGNLKVMSEMLTELVPGQENPDDLELLQELNSTCramqQRVVELISQV-----SNEEVTEELLRVNDDLNNV 78