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 1802669874  63 LQRYIQNACDPQNFEPNLALSLEIADLINAKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTK 142
Cdd:cd16998     1 LQRYIERACDPSLEEPNLALNLEIADLINEKQGNTPREAAFAIVRLVNSRNPTVALLALHLLDVCVKNCGYPFHLQIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1802669874 143 EFLNELVRRFPERPAVRPTRVQHKILELIEEWRCTICKTSKYKEDLGFIRDMHRLLSYK 201
Cdd:cd16998    81 EFLNELVRRFPERPPSRLNPVQHKILELIEEWKQTLCKTSRYKEDLGHIRDMHRLLSYK 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 1802669874  596 NSNIRTVFTVSRPSGAndwLSVESKISNNTAQPISDLTFQLAVTKGYSLKLEPQSSRNLGPNQKdgITQSIKVQGVnrgT 675
Cdd:smart00809   4 KNGLQIGFKFERRPGL---IRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ--ITQVLKVENP---G 75

                           90       100
                   ....*....|....*....|....*....
gi 1802669874  676 GQSVKMRWRASYSVAGQQQQdEQGMVESL 704
Cdd:smart00809  76 KFPLRLRLRLSYLLGGSAVT-EQGDVLKF 103

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 1802669874  63 LQRYIQNACDPQNFEPNLALSLEIADLINAKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTK 142
Cdd:cd16998     1 LQRYIERACDPSLEEPNLALNLEIADLINEKQGNTPREAAFAIVRLVNSRNPTVALLALHLLDVCVKNCGYPFHLQIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1802669874 143 EFLNELVRRFPERPAVRPTRVQHKILELIEEWRCTICKTSKYKEDLGFIRDMHRLLSYK 201
Cdd:cd16998    81 EFLNELVRRFPERPPSRLNPVQHKILELIEEWKQTLCKTSRYKEDLGHIRDMHRLLSYK 139

Domain present in VPS-27, Hrs and STAM; Unpublished observations.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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874   63 LQRYIQNACDPQNFEPNLALSLEIADLINaKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTK 142
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLIN-STPDGPKDAVRLLKKRLNNKNPHVALLALTLLDACVKNCGSKFHLEVASK 79

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874  143 EFLNELVRRFPERPAVRptRVQHKILELIEEWRCTIcktsKYKEDLGFIRDMHRLLSYKG 202
Cdd:smart00288  80 EFLNELVKLIKPKYPLP--LVKKRILELIQEWADAF----KNDPDLSQIVDVYDLLKKKG 133

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 1802669874 285 QQKARLLEEMLQGYKQgDEIKEGDVFEELANALASAQPKIQRMCEEESEDHEAVAKLFEINDSIHRTIQRYKLVK 359
Cdd:pfam03127   1 RNNAKLLNEMLSSTDP-DEELDNELIKELYERCKSAQPKIQKLIEETSDEDDLLAELLQLNDDLNNVLERYERLK 74

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 1802669874 596 NSNIRTVFTVSRPSGANDwLSVESKISNNTAQPISDLTFQLAVTKGYSLKLEPQSSRNLGPNQKDGITQSIKVQGVNRGT 675
Cdd:pfam02883   8 SDGLQIGFSFERSRRPGQ-IRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNPGGQITQVLLIENPGKKP 86

                          90       100
                  ....*....|....*....|....*....
gi 1802669874 676 gqsVKMRWRASYSVAGQQQqdEQGMVESL 704
Cdd:pfam02883  87 ---LRMRLKISYLNGGAVQ--EQGDVLKF 110

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 1802669874  63 LQRYIQNACDPQNFEPNLALSLEIADLINAKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTK 142
Cdd:cd16998     1 LQRYIERACDPSLEEPNLALNLEIADLINEKQGNTPREAAFAIVRLVNSRNPTVALLALHLLDVCVKNCGYPFHLQIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1802669874 143 EFLNELVRRFPERPAVRPTRVQHKILELIEEWRCTICKTSKYKEDLGFIRDMHRLLSYK 201
Cdd:cd16998    81 EFLNELVRRFPERPPSRLNPVQHKILELIEEWKQTLCKTSRYKEDLGHIRDMHRLLSYK 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874   63 LQRYIQNACDPQNFEPNLALSLEIADLINaKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTK 142
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLIN-STPDGPKDAVRLLKKRLNNKNPHVALLALTLLDACVKNCGSKFHLEVASK 79

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874  143 EFLNELVRRFPERPAVRptRVQHKILELIEEWRCTIcktsKYKEDLGFIRDMHRLLSYKG 202
Cdd:smart00288  80 EFLNELVKLIKPKYPLP--LVKKRILELIQEWADAF----KNDPDLSQIVDVYDLLKKKG 133

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 1802669874 272 DYRAKAAEEVGKIQQKARLLEEMLQGYKQGDEIKEGDVFEELANALASAQPKIQRMCEEESEDHEAVAKLFEINDSIHRT 351
Cdd:cd14235     1 DYKAQVAEELEKLKRKAILLNEMLNNATPGEIDVEGDTYDELASSLKSAQPKIQKIIEEESEDEESVQKLLELNDLINSL 80

                          90
                  ....*....|..
gi 1802669874 352 IQRYKLVKVGDL 363
Cdd:cd14235    81 LERYDLLKKGDA 92

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 1802669874  77 EPNLALSLEIADLINAKKgNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTKEFLNELVrRFPERP 156
Cdd:cd16979    19 EEDLALALEISDLIRSKS-VPPKDAMRSLKKRILHKNPNVQLLALKLTDVCVKNGGDHFLVEIASREFMDNLV-SLIRST 96

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|
gi 1802669874 157 AVRPTrVQHKILELIEEWRCtickTSKYKEDLGFIRDMHRLLSYKGYVFP 206
Cdd:cd16979    97 GVNPE-VKEKILRLIQEWAL----AFKSKSQLSYVVEVYKKLKSEGIEFP 141

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 1802669874  67 IQNACDPQNFEPNLALSLEIADLINaKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTKEFLN 146
Cdd:cd03568     5 VEKATSEKNTSENWSLILDICDKVG-RSPNGAKDCLKSIMKRLNHKDPHVALQALTLLDACVKNCGKIFHLEVCSRDFES 83

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1802669874 147 ELVRRFPER-PAVRptrvqHKILELIEEWRCTICKT 181
Cdd:cd03568    84 ELRKLLTKShPKVA-----EKLKELLKKWAEEEFKD 114

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 1802669874  79 NLALSLEIADLINAKKgNAPREAAVSI----VQYVNhRNPNVSLLALSLLDICVKNCGYPFHLQISTKEFLNELVRRF-P 153
Cdd:cd03565    18 DWALNMEICDMINETD-DGPKDAIKAIkkrlSTNAG-KNHTVVMYTLTLLETCVKNCGHRFHVLVANKDFLQELVKLIgP 95

                          90       100
                  ....*....|....*....|.
gi 1802669874 154 ERPAvrPTRVQHKILELIEEW 174
Cdd:cd03565    96 KNDP--PTIVQEKVLSLIQSW 114

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 1802669874  67 IQNACDPQNFEPNLALSLEIADLINAKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTKEFLN 146
Cdd:cd16978     5 IIKATDETLTSENWQYILDVCDKVNSDPEDGAREAIAAIQKRLQHRNANVQLRSLSLADALAKNCGSRLHQEISSRSFTQ 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*..
gi 1802669874 147 ELVRRFPERpAVRPTrVQHKILELIEEWRcticKTSKYKEDLGFIRD 193
Cdd:cd16978    85 TLLRLINDR-TTHAT-VKKRILELIKQLS----DSFKSDPSLGLMSD 125

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 1802669874  62 PLQRYIQNACDPQNFEPNLALSLEIADLINaKKGNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQIST 141
Cdd:cd03567     1 SLEYLLNKATNPFNTEEDWEAIDAFCDRVN-KEPEGPQIAVRLLAHKIQSPNEKEALRALTVLEACVKNCGPRFHSEVGK 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1802669874 142 KEFLNELVR---------RFPErpavrptRVQHKILELIEEWRCTICKTSKYKE 186
Cdd:cd03567    80 FRFLNELIKlvspkylgnRTPE-------EVKQKIIELLYSWTRSLPHEPKIKE 126

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 1802669874  62 PLQRYIQNACDPQNFEPNLALSLEIADLINAKKgNAPREAAVSIVQYVN-HRNPNVSLLALSLLDICVKNCGYPFHLQIS 140
Cdd:cd16996     1 PVGQCIEKATDGSLQSEDWTLNMEICDIINETE-EGPKDAIRALKKRLNgNKNYREVMLALTVLETCVKNCGHRFHVLVA 79

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1802669874 141 TKEFLNELVRRFPERPAVRPTRVQHKILELIEEW 174
Cdd:cd16996    80 SRDFIDGVLVKIISPKNNPPTIVQDKVLALIQAW 113

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 1802669874  67 IQNACDPQNFEPNLALSLEIADLINAKKgNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTKEFLN 146
Cdd:cd16999     5 VEKATNEYNTSEDWSLIMDICDKVGSTP-NGAKDCLKAIMKRVNHKVPHVALQALTLLGACVSNCGKIFHLEVCSRDFAT 83

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1802669874 147 ELvrRFPERPAVRPtRVQHKILELIEEWrctickTSKYKED--LGFIRDMHRLLSYKGYVFP 206
Cdd:cd16999    84 EV--RAVIKNKAHP-KVCEKLKALMVEW------SEEFQKDpqFSLISATIKSLKEEGITFP 136

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874 280 EVGKIQQKARLLEEMLQGYKQGDEIKEG-DVFEELANALASAQPKIQRMCEEESEDHEAVAKLFEINDSIHRTIQRYKLV 358
Cdd:cd14230     1 TLEEAKNNVDLLDEMLLSYSQEDSSDGDnELMKELYDQLENMRPTLFKLASETEENDNSLGDVLQASDNVNRVINKYKDI 80

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 1802669874  67 IQNACDPQNFEPNLALSLEIADLINAKKgNAPREAAVSIVQYVNHRNPNVSLLALSLLDICVKNCGYPFHLQISTKEFLN 146
Cdd:cd17000     5 VEKATSEMNTAEDWGLILDICDKVGQSR-TGPKDCLRSIMRRVNHKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDFAS 83

                  ..
gi 1802669874 147 EL 148
Cdd:cd17000    84 EV 85

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874  59 APTPLQR-----YIQNACDPQNFEPNlalSLEIADLINAKKGNAPREAAvsivqyvnhrnpnvSLLALSLLDICVKNCGY 133
Cdd:cd17009     9 ATNPLNKeldwaSINGFCEQLNEEFE---GPPLATRLLAHKIQSPQEWE--------------AIQALTVLETCMKSCGK 71

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1802669874 134 PFHLQISTKEFLNELVRRF-PERPAVR-PTRVQHKILELIEEWRCTICKTSKykedlgfIRDMHRLLSYKGYV 204
Cdd:cd17009    72 RFHDEVGKFRFLNELIKVVsPKYLGSRtPEKVKNKILELLYSWTVGLPEEVK-------IAEAYQMLKKQGIV 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874  86 IADLINAKKgNAPREAAVS----IVQYVNHRNPNvslLALSLLDICVKNCGYPFHLQISTKEFLNELVRRFPERPAVRPT 161
Cdd:cd16997    25 ICDIINTTE-DGPKDAVKAlkkrISKNYNHKEIR---LTLSLLDMCMQNCGPSFQSLVVKKEFVKDVLVKLLNPRYNLPV 100

                          90
                  ....*....|...
gi 1802669874 162 RVQHKILELIEEW 174
Cdd:cd16997   101 DLQNKILNFIMTW 113

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).

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1802669874 270 KTDYRAKAAEEVgkiQQKARLLEEMLQGYKQGDEIKEG-DVFEELANALASAQPKIQRMCEEESEDHEAVAKLFEINDSI 348
Cdd:cd14239     1 KVSKRVNAIEEV---NNNVKLLTEMLMSYSRGELSESSeELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNL 77

                  ....*...
gi 1802669874 349 HRTIQRYK 356
Cdd:cd14239    78 TQVINLYK 85

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
                  ....*....|....*....|....*....|...
gi 1802669874 236 QSAKLQELIRRGTPHDLQEANKLMKIMAGYDNR 268
Cdd:pfam18308   6 KSKLLARLLKSKNPEDLQAANRLIKSMVKEDDE 38