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 530409942 122 QIARLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 201
Cdd:cd14238    3 QIARLRSELDIVRGNTKVMSEMLTEMVPGQEDPSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 82

                         90
                 ....*....|
gi 530409942 202 LRYERFERYR 211
Cdd:cd14238   83 LRYERFERYR 92

canonical GAT domain found in target of Myb-like protein 2 (Tom1L2); Tom1L2, together with Myb protein 1 (Tom1) and target of Myb-like protein 1 (Tom1L1), constitute the Tom1 family. Tom1L2 can interact with Toll-interacting protein (Tollip), clathrin, and ubiquitin. It may play a potential role in endosomal sorting, as well as in the regulation of membrane trafficking that is linked to immunity and cell proliferation. Tom1L2 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain, a GAT (GGA and TOM1) domain, and a C-terminal clathrin-binding region, both of which are conserved in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs). It interacts with Tollip through their GAT domain and recuits clathrin onto endosomes through their C-terminal region. However, in the C-terminal clathrin-binding region, Tom1 and Tom1L2 are similar to each other, but distinguishable from Tom1L1. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942 122 QIARLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 201
Cdd:cd14238    3 QIARLRSELDIVRGNTKVMSEMLTEMVPGQEDPSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 82

                         90
                 ....*....|
gi 530409942 202 LRYERFERYR 211
Cdd:cd14238   83 LRYERFERYR 92

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942   12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHILVAN 91
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRIN-SPNPHVALLALTLLDACVKNCGSKFHLEIAS 79

                          90       100       110
                  ....*....|....*....|....*....|..
gi 530409942   92 RDFIDSVLVKIISPKNNPPTIVQDKVLALIQI 123
Cdd:pfam00790  80 KEFLNELVKLIPNKPYGKPAKVKKKILELIQE 111

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942  12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNRNYREVMLALTVLETCVKNCGHRFHILVAN 91
Cdd:cd16995    1 PVGQRIEKATDGSLQSEDWGLNMEICDIINETEEGPKDAIRAIKKRIVGNKNFREVMLALTVLETCVKNCGHRFHVLVAS 80

                         90       100       110
                 ....*....|....*....|....*....|.
gi 530409942  92 RDFIDSVLVKIISPKNNPPTIVQDKVLALIQ 122
Cdd:cd16995   81 QDFVEGVLVKTILPKNNPPAIVHDKVLNLIQ 111

canonical GAT domain found in target of Myb-like protein 2 (Tom1L2); Tom1L2, together with Myb protein 1 (Tom1) and target of Myb-like protein 1 (Tom1L1), constitute the Tom1 family. Tom1L2 can interact with Toll-interacting protein (Tollip), clathrin, and ubiquitin. It may play a potential role in endosomal sorting, as well as in the regulation of membrane trafficking that is linked to immunity and cell proliferation. Tom1L2 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain, a GAT (GGA and TOM1) domain, and a C-terminal clathrin-binding region, both of which are conserved in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs). It interacts with Tollip through their GAT domain and recuits clathrin onto endosomes through their C-terminal region. However, in the C-terminal clathrin-binding region, Tom1 and Tom1L2 are similar to each other, but distinguishable from Tom1L1. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942 122 QIARLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 201
Cdd:cd14238    3 QIARLRSELDIVRGNTKVMSEMLTEMVPGQEDPSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 82

                         90
                 ....*....|
gi 530409942 202 LRYERFERYR 211
Cdd:cd14238   83 LRYERFERYR 92

canonical GAT domain found in target of Myb protein 1 (Tom1); Tom1 was originally identified by its induced expression by the v-Myb oncogene. It is predominantly present in the cytosol and can interact with clathrin, endofin, Toll-interacting protein (Tollip), and ubiquitinated proteins. It acts as a linker protein to regulate the ability of endofin to recruit clathrin onto the sorting endosome. Moreover, Tom1 functions as a negative regulator of IL-1beta and tumor necrosis factor (TNF)-alpha-induced signaling pathways. It also plays a role in the TLR2/4 signaling pathways. Tom1 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain, a GAT (GGA and TOM1) domain and a C-terminal clathrin-binding region, both of which are conserved in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs). In contrast to GGAs, Tom1 binds to ubiquitin, ubiquitinated proteins, and Tollip through its GAT domain, but does not associate with Arf GTPases through its GAT domain nor with acidic cluster-dileucine sequences through its VHS domain. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942 122 QIARLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVF 201
Cdd:cd14236    3 QIGKLRSELEMVSGNVRVMSEMLTELVPTQAEPADLELLQELNRTCRAMQQRVLELIPQIANEQLTEELLIVNDNLNNVF 82

                         90
                 ....*....|...
gi 530409942 202 LRYERFERYRSGR 214
Cdd:cd14236   83 LRHERFERFRTGQ 95

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942   12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHILVAN 91
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRIN-SPNPHVALLALTLLDACVKNCGSKFHLEIAS 79

                          90       100       110
                  ....*....|....*....|....*....|..
gi 530409942   92 RDFIDSVLVKIISPKNNPPTIVQDKVLALIQI 123
Cdd:pfam00790  80 KEFLNELVKLIPNKPYGKPAKVKKKILELIQE 111

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 530409942  12 PVGQCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNRNYREVMLALTVLETCVKNCGHRFHILVAN 91
Cdd:cd16997    1 SVGHLIEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRISKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVK 80

                         90       100       110
                 ....*....|....*....|....*....|..
gi 530409942  92 RDFIDSVLVKIISPKNNPPTIVQDKVLALIQI 123
Cdd:cd16997   81 KEFVKDVLVKLLNPRYNLPVDLQNKILNFIMT 112

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 530409942 121 IQIARLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNV 200
Cdd:cd14237    2 EQIGKLYSELDIVKMNVRVMSAILLENTPGAENPEDMELLEKLYKTCREMQERIMKLLETVENEDVIIELIQVNDDLNNV 81

                         90
                 ....*....|.
gi 530409942 201 FLRYERFERYR 211
Cdd:cd14237   82 FLRHERFSRNR 92

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942  16 CLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHILVANRDFI 95
Cdd:cd03569    6 LLDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLN-DQNPHVALYALQVLESVVKNCGTPVHDEVATKEFM 84

                         90       100
                 ....*....|....*....|....*....
gi 530409942  96 DSV--LVKIISPKNnpptiVQDKVLALIQ 122
Cdd:cd03569   85 EELrdLVKTTTSEN-----VRNKILELIQ 108

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 530409942  11 TPVGQCLEKATDGSL--QSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHIL 88
Cdd:cd16979    1 SEFDELIEKATSESIpnGEEDLALALEISDLIRSKSVPPKDAMRSLKKRIL-HKNPNVQLLALKLTDVCVKNGGDHFLVE 79

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 530409942  89 VANRDFIDSvLVKII-SPKNNPPtiVQDKVLALIQ 122
Cdd:cd16979   80 IASREFMDN-LVSLIrSTGVNPE--VKEKILRLIQ 111

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 530409942  17 LEKATDGSLQSEDWTLNMEICDIINETE-EGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHILVANRDFI 95
Cdd:cd16998    5 IERACDPSLEEPNLALNLEIADLINEKQgNTPREAAFAIVRLVN-SRNPTVALLALHLLDVCVKNCGYPFHLQIASKEFL 83

                         90       100       110
                 ....*....|....*....|....*....|
gi 530409942  96 DSvLVKIIsPkNNPPTI---VQDKVLALIQ 122
Cdd:cd16998   84 NE-LVRRF-P-ERPPSRlnpVQHKILELIE 110

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 530409942  15 QCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHILVANRDF 94
Cdd:cd16999    3 QDVEKATNEYNTSEDWSLIMDICDKVGSTPNGAKDCLKAIMKRVN-HKVPHVALQALTLLGACVSNCGKIFHLEVCSRDF 81

                         90       100
                 ....*....|....*....|....*..
gi 530409942  95 IDSVLvKIISPKNNPPtiVQDKVLALI 121
Cdd:cd16999   82 ATEVR-AVIKNKAHPK--VCEKLKALM 105

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 530409942 131 DVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVFLRYERF 207
Cdd:cd12930    1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLNDKADDQKYNTLLE*NDNLSEV*NIYDRL 77

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 530409942  17 LEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNRNYrEVMLALTVLETCVKNCGHRFHILVANRDFID 96
Cdd:cd17008    8 LNKATNPSNRQEDWEYIIGFCDQINKELEGPQIAVRLLAHKIQSPQEW-EALQALTVLEACMKNCGRRFHNEVGKFRFLN 86

                         90       100
                 ....*....|....*....|....*...
gi 530409942  97 SvLVKIISPK---NNPPTIVQDKVLALI 121
Cdd:cd17008   87 E-LIKVVSPKylgDRVSEKVKTKVIELL 113

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 530409942  17 LEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNRNyREVMLALTVLETCVKNCGHRFHILVANRDFID 96
Cdd:cd17010    6 LNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQE-REALHALTVLEMCMNNCGERFHSEVAKFRFLN 84

                         90
                 ....*....|
gi 530409942  97 SvLVKIISPK 106
Cdd:cd17010   85 E-LIKVLSPK 93

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.

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                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530409942  15 QCLEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNgNRNYREVMLALTVLETCVKNCGHRFHILVANRDF 94
Cdd:cd17000    3 QDVEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVN-HKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDF 81

                 ....
gi 530409942  95 IDSV 98
Cdd:cd17000   82 ASEV 85

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

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gi 530409942 125 RLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVS-NEEVTEELLHVNDDLNNVFLR 203
Cdd:cd14234    1 KRLLELEEVNNNVKLLNEMLDHYSPGESSQDELELMKELYESCEKMRPTLFRLASETDdDDEGLADILQANDELTRVMQR 80

                 ...
gi 530409942 204 YER 206
Cdd:cd14234   81 YKN 83

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

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gi 530409942 124 ARLRSELDVVRGNTKVMSEMLTEMVPGQEDSSDlELLQELNRTCRAMQQRIVELISRVSN-EEVTEELLHVNDDLNNVFL 202
Cdd:cd14235    4 AQVAEELEKLKRKAILLNEMLNNATPGEIDVEG-DTYDELASSLKSAQPKIQKIIEEESEdEESVQKLLELNDLINSLLE 82

                 ...
gi 530409942 203 RYE 205
Cdd:cd14235   83 RYD 85

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

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gi 530409942 130 LDVVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQQRIVELISRVS-NEEVTEELLHVNDDLNNVFLRYER 206
Cdd:cd14240    6 LEEVNNNVRLLNEMLAHYSKEDSSDGDKELMKELYDRCEKKRRTLFKLASETEdNDNSLGDILQASDDLSRVINSYKK 83

canonical GAT domain found in yeast LAS seventeen-binding protein 5 (Lsb5p) and similar proteins; Lsb5p, also called LAS17-binding protein 5, is a Golgi-localized gamma ear-containing Arf-binding protein (GGA)-like protein located to the plasma membrane in an actin-independent manner. It plays important roles in membrane-trafficking events through association with the actin regulators, the yeast Wiskott-Aldrich syndrome protein (WASP) homologue Las17p and the cortical protein Sla1p, the yeast Arf3p (orthologous with mammalian Arf6), and ubiquitin. Lsb5p contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. In contrast to GGA proteins, Lsb5p harbors a C-terminal NPF (Asn-Pro-Phe) motif, but does not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

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gi 530409942 149 PGQEDSSDLELLQELNRTCRAMQQRIVELISRVSNEEVTEELLHVNDDLNNVFLRYER 206
Cdd:cd14232   20 RETERVSDDAEVQERFEKCKQLRRKILRYIQLVEDEEYLGSLLHANEELVAALEAYDE 77