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 1945886613 220 DYAEQASSELDKILQKAVLLTEMLNDVKPGEIIGRGDIFEDLLGTCKAAQPKIQKFI-NEGEDVENMEKLLEINDIINNV 298
Cdd:cd14235     1 DYKAQVAEELEKLKRKAILLNEMLNNATPGEIDVEGDTYDELASSLKSAQPKIQKIIeEESEDEESVQKLLELNDLINSL 80

                          90
                  ....*....|..
gi 1945886613 299 IQQYGQVKSGNL 310
Cdd:cd14235    81 LERYDLLKKGDA 92

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 1945886613 184 QSAKLQELIRRGRPEDVLAANELVKKMTGYEQE 216
Cdd:pfam18308   6 KSKLLARLLKSKNPEDLQAANRLIKSMVKEDDE 38

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKEKQkNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATK 90
Cdd:pfam00790   2 LERWIDKATDPSLREEDWSLILDICDLINETE-TGPKEAVRLIKKRINSPNPHVALLALTLLDACVKNCGSKFHLEIASK 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1945886613  91 EFLNELVRKFPERPLAVPTPVQSKILEMIQEWYETLCRnsryKEDLIHIRDMHRLLGFKG 150
Cdd:pfam00790  81 EFLNELVKLIPNKPYGKPAKVKKKILELIQEWADAFKN----DPDLKYIRDMYKLLKRKG 136

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 1945886613 220 DYAEQASSELDKILQKAVLLTEMLNDVKPGEIIGRGDIFEDLLGTCKAAQPKIQKFI-NEGEDVENMEKLLEINDIINNV 298
Cdd:cd14235     1 DYKAQVAEELEKLKRKAILLNEMLNNATPGEIDVEGDTYDELASSLKSAQPKIQKIIeEESEDEESVQKLLELNDLINSL 80

                          90
                  ....*....|..
gi 1945886613 299 IQQYGQVKSGNL 310
Cdd:cd14235    81 LERYDLLKKGDA 92

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 1945886613 496 TVVLLNKNGLQIELDIEYESQDGTaIKVMAYFSNSLNSAMSNLTFRVAVPKSLQLKLEPQSAQVVNAFSKRTVTQAMSIK 575
Cdd:pfam02883   2 PVVLYESDGLQIGFSFERSRRPGQ-IRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNPGGQITQVLLIE 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1945886613 576 NPtQQNPVRMRYHVSYvLAGRTIEEQGEFNQFP 608
Cdd:pfam02883  81 NP-GKKPLRMRLKISY-LNGGAVQEQGDVLKFP 111

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 1945886613 184 QSAKLQELIRRGRPEDVLAANELVKKMTGYEQE 216
Cdd:pfam18308   6 KSKLLARLLKSKNPEDLQAANRLIKSMVKEDDE 38

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKEKQkNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATK 90
Cdd:pfam00790   2 LERWIDKATDPSLREEDWSLILDICDLINETE-TGPKEAVRLIKKRINSPNPHVALLALTLLDACVKNCGSKFHLEIASK 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1945886613  91 EFLNELVRKFPERPLAVPTPVQSKILEMIQEWYETLCRnsryKEDLIHIRDMHRLLGFKG 150
Cdd:pfam00790  81 EFLNELVKLIPNKPYGKPAKVKKKILELIQEWADAFKN----DPDLKYIRDMYKLLKRKG 136

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 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKEKqKNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATK 90
Cdd:cd16977     1 LERWINRATNPSNAEPDWALILGFCDQINED-GEGPRDAARLLAHKIQSPQEWEAIQALTVLEVCMKNCGYRFHLEVGKF 79

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1945886613  91 EFLNELVRKFPERPLAVPT--PVQSKILEMIQEWYETLCrnsrykeDLIHIRDMHRLLGFK 149
Cdd:cd16977    80 RFLNELIKVVSPKYLGSRRseKVKRKILELLYSWTVTLP-------EEGKIRDAYQMLKKQ 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 1945886613 220 DYAEQASSELDKILQKAVLLTEMLNDVKPGEIIGRGDIFEDLLGTCKAAQPKIQKFI-NEGEDVENMEKLLEINDIINNV 298
Cdd:cd14235     1 DYKAQVAEELEKLKRKAILLNEMLNNATPGEIDVEGDTYDELASSLKSAQPKIQKIIeEESEDEESVQKLLELNDLINSL 80

                          90
                  ....*....|..
gi 1945886613 299 IQQYGQVKSGNL 310
Cdd:cd14235    81 LERYDLLKKGDA 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 1945886613  15 IERACDPSRYEPDLALNLEICDVIKEkQKNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATKEFLN 94
Cdd:cd03569     7 LDKATSQLLLEPDWESILQICDLIRQ-GDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVATKEFME 85

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1945886613  95 ELvRKFPERplAVPTPVQSKILEMIQEWYETLCRNSRYKedliHIRDMHRLLGFKGYRFP 154
Cdd:cd03569    86 EL-RDLVKT--TTSENVRNKILELIQAWAHAFRNEPKYK----IVQDTYNIMKMEGYKFP 138

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 1945886613  499 LLNKNGLQIELDIEYESQdgtAIKVMAYFSNSLNSAMSNLTFRVAVPKSLQLKLEPQSAQVVNAFSkrTVTQAMSIKNPt 578
Cdd:smart00809   1 AYEKNGLQIGFKFERRPG---LIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGG--QITQVLKVENP- 74

                           90       100       110
                   ....*....|....*....|....*....|
gi 1945886613  579 QQNPVRMRYHVSYVLAGRTIEEQGEFNQFP 608
Cdd:smart00809  75 GKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

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 1945886613 496 TVVLLNKNGLQIELDIEYESQDGTaIKVMAYFSNSLNSAMSNLTFRVAVPKSLQLKLEPQSAQVVNAFSKRTVTQAMSIK 575
Cdd:pfam02883   2 PVVLYESDGLQIGFSFERSRRPGQ-IRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNPGGQITQVLLIE 80

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1945886613 576 NPtQQNPVRMRYHVSYvLAGRTIEEQGEFNQFP 608
Cdd:pfam02883  81 NP-GKKPLRMRLKISY-LNGGAVQEQGDVLKFP 111

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 1945886613  15 IERACDPSRYEPDLALNLEICDVIKEKQKNtPREAAIYIV-RLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATKEFL 93
Cdd:cd16996     6 IEKATDGSLQSEDWTLNMEICDIINETEEG-PKDAIRALKkRLNGNKNYREVMLALTVLETCVKNCGHRFHVLVASRDFI 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1945886613  94 NELVRKFPERPLAVPTPVQSKILEMIQEWYETLcRNSRYKEDLIHI 139
Cdd:cd16996    85 DGVLVKIISPKNNPPTIVQDKVLALIQAWADAF-RSSPDLTGVVHI 129

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 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKEKQkNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATK 90
Cdd:cd00197     1 FEKTVEKATSNENMGPDWPLIMEICDLINETN-VGPKEAVDAIKKRINNKNPHVVLKALTLLEYCVKNCGERFHQEVASN 79

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1945886613  91 EFLNElVRKFPERPL---AVPTPVQSKILEMIQEW 122
Cdd:cd00197    80 DFAVE-LLKFDKSGLlgdDVSTNVREKAIELVQLW 113

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 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKEKQKNTPREA-AIYIVRLVnSRNMHVGMLALALLDNCVKNCGYPFHLQIAT 89
Cdd:cd16978     1 IDELIIKATDETLTSENWQYILDVCDKVNSDPEDGAREAiAAIQKRLQ-HRNANVQLRSLSLADALAKNCGSRLHQEISS 79

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1945886613  90 KEFLNELVRKFPERplAVPTPVQSKILEMIQEWYET 125
Cdd:cd16978    80 RSFTQTLLRLINDR--TTHATVKKRILELIKQLSDS 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 1945886613  15 IERACDPSRYEPDLALNLEICDVIKeKQKNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATKEFLN 94
Cdd:cd16999     5 VEKATNEYNTSEDWSLIMDICDKVG-STPNGAKDCLKAIMKRVNHKVPHVALQALTLLGACVSNCGKIFHLEVCSRDFAT 83

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1945886613  95 ELVRKFPERplAVPTpVQSKILEMIQEWYETLCRNSRY 132
Cdd:cd16999    84 EVRAVIKNK--AHPK-VCEKLKALMVEWSEEFQKDPQF 118

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 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKEKQKNtPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATK 90
Cdd:cd17009     2 LEARINRATNPLNKELDWASINGFCEQLNEEFEG-PPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 80

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1945886613  91 EFLNELVRKFPERPLA--VPTPVQSKILEMIQEW 122
Cdd:cd17009    81 RFLNELIKVVSPKYLGsrTPEKVKNKILELLYSW 114

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 1945886613  11 LETYIERACDPSRYEPDLALNLEICDVIKeKQKNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATK 90
Cdd:cd17010     2 LESWLNKATDPSNSEEDWECIQGFCEQVN-KEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKF 80

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1945886613  91 EFLNELVRKFPERPLAVPT--PVQSKILEMIQEWyetlcrnSRYKEDLIHIRDMHRLLGFKG 150
Cdd:cd17010    81 RFLNELIKVLSPKYLGTWSseKVKSRVIEVLFSW-------TVWLPEEVKIRDAYQMLKKQG 135

canonical GAT domain found in eukaryotic ADP-ribosylation factor (Arf)-binding proteins (GGAs), metazoan myb protein 1 (Tom1)-like proteins, and similar proteins; This model represents the canonical GAT (GGA and Tom1) domain found in GGAs from eukaryotes, 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. In addition, Tom1 family proteins recruit clathrin onto endosomes through their C-terminal region. The C-terminal clathrin-binding region of Tom1 and Tom1L2 are similar to each other, but distinguishable from Tom1L1.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1945886613 228 ELDKILQKAVLLTEMLNDVKPGEIiGRGDIFEDLLGTCKAAQPKIQKFINEGEDVEN---MEKLLEINDIINNVIQQY 302
Cdd:cd21383     1 DLEEVKENASLLNEMLSAASPEEL-LDNELLQELVEFCRACQPRIVELIEATTDGLDedtLEELLELNDELNEALQRY 77

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 1945886613  15 IERACDPSRYEPDLALNLEICDVIKEKQKNTPREAAIYIVRLVNSRNMHVGMLALALLDNCVKNCGYPFHLQIATKEFLN 94
Cdd:cd16997     6 IEKATFGTVQTEDWGQFMHICDIINTTEDGPKDAVKALKKRISKNYNHKEIRLTLSLLDMCMQNCGPSFQSLVVKKEFVK 85

                          90       100
                  ....*....|....*....|....*...
gi 1945886613  95 ELVRKFPERPLAVPTPVQSKILEMIQEW 122
Cdd:cd16997    86 DVLVKLLNPRYNLPVDLQNKILNFIMTW 113

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 1945886613 219 PDYAEQASSELDKILQKAVLLTEMLNDVKPGEIIGRG-DIFEDLLGTCKAAQPKIQKFINEGEDVENMEKLLEINDIINN 297
Cdd:cd14236     1 PEQIGKLRSELEMVSGNVRVMSEMLTELVPTQAEPADlELLQELNRTCRAMQQRVLELIPQIANEQLTEELLIVNDNLNN 80

                          90
                  ....*....|....
gi 1945886613 298 VI---QQYGQVKSG 308
Cdd:cd14236    81 VFlrhERFERFRTG 94

canonical GAT domain found in uncharacterized Golgi-localized gamma ear-containing Arf-binding protein (GGA)-like proteins mainly found in plants; The family includes a group of uncharacterized plant proteins containing an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. Both domains are also present in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs), 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. In contrast to GGA proteins, members in this family do 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.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1945886613 238 LLTEMLNDVKPGEIIG-RGDIFEDLLGTCKAAQPKIQKFINEGEDVENMEKLLEINDIINNVIQQY 302
Cdd:cd14231    11 LLSDMLNAVDPRDPEAlKDELTVDLVEQCRQSQPRVMQLVESTGDEGLLFQALELNDELQRVLSKH 76

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1945886613 239 LTEMLNDVKPGEI-IGRGDIFEDLLGTCKAAQPKIQKFINEGEDVENMEKLLEINDIINNVIQQY 302
Cdd:cd12930    10 FSELLEK*KSRPLeILDDELLQELAQRCFASKARLNYLLNDKADDQKYNTLLE*NDNLSEV*NIY 74