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 213688377  29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:cd17010    2 LESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKFR 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 213688377 109 FLNELIKVLSPKYLGAWATEKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGIIKQ 166
Cdd:cd17010   82 FLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIKQ 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377   482 VYDRNGFRILLHFSQtgapgHPDVQVLLLTMMSTATQPVWDVMFQVAVPKSMRVKLQPASSSKLPAFSPltppavISQML 561
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 213688377   562 LLDNPHKEPIRLRYKLTFNQGGQPFSEVGEVKDFP 596
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377  29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:cd17010    2 LESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKFR 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 213688377 109 FLNELIKVLSPKYLGAWATEKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGIIKQ 166
Cdd:cd17010   82 FLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIKQ 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377    29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLINSTPDGPKDAVRLLKKRLNNKNPHVALLALTLLDACVKNCGSKFHLEVASKE 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 213688377   109 FLNELIKVLSPKYLGawatEKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 162
Cdd:smart00288  81 FLNELVKLIKPKYPL----PLVKKRILELIQEWADAFkndPDLSQIVDVYDLLKKKG 133

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377   482 VYDRNGFRILLHFSQtgapgHPDVQVLLLTMMSTATQPVWDVMFQVAVPKSMRVKLQPASSSKLPAFSPltppavISQML 561
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 213688377   562 LLDNPHKEPIRLRYKLTFNQGGQPFSEVGEVKDFP 596
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

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

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 213688377  187 FDaDEEKSKLLTRLLKSNHPEDLQAANRLIKNLVKEEQEK 226
Cdd:pfam18308   1 FD-DEEKSKLLARLLKSKNPEDLQAANRLIKSMVKEDDER 39

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 213688377  29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:cd17010    2 LESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKFR 81

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 213688377 109 FLNELIKVLSPKYLGAWATEKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGIIKQ 166
Cdd:cd17010   82 FLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIKQ 139

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377  29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:cd16977    1 LERWINRATNPSNAEPDWALILGFCDQINEDGEGPRDAARLLAHKIQSPQEWEAIQALTVLEVCMKNCGYRFHLEVGKFR 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 213688377 109 FLNELIKVLSPKYLGAWATEKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQ 161
Cdd:cd16977   81 FLNELIKVVSPKYLGSRRSEKVKRKILELLYSWTVTLPEEGKIRDAYQMLKKQ 133

VHS (Vps27/Hrs/STAM) domain of ADP-ribosylation factor-binding protein GGA1; ADP-ribosylation factor-binding protein GGA1 (Golgi-localized, Gamma-ear-containing, Arf-binding 1) is also called Gamma-adaptin-related protein 1. It is expressed in human brain and affects the generation of amyloid beta-peptide, and may be involved in the pathogenesis of Alzheimer disease. It is a member of the GGA subfamily, which is comprised of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377  28 ALELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKF 107
Cdd:cd17009    1 TLEARINRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 213688377 108 RFLNELIKVLSPKYLGAWATEKVKGRVIEILFSWTVWFPEDIKIRDAYQMLKKQGIIKQ 166
Cdd:cd17009   81 RFLNELIKVVSPKYLGSRTPEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 139

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377    29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:smart00288   1 VERLIDKATSPSLLEEDWELILEICDLINSTPDGPKDAVRLLKKRLNNKNPHVALLALTLLDACVKNCGSKFHLEVASKE 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 213688377   109 FLNELIKVLSPKYLGawatEKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 162
Cdd:smart00288  81 FLNELVKLIKPKYPL----PLVKKRILELIQEWADAFkndPDLSQIVDVYDLLKKKG 133

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377   482 VYDRNGFRILLHFSQtgapgHPDVQVLLLTMMSTATQPVWDVMFQVAVPKSMRVKLQPASSSKLPAFSPltppavISQML 561
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 213688377   562 LLDNPHKEPIRLRYKLTFNQGGQPFSEVGEVKDFP 596
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

VHS (Vps27/Hrs/STAM) domain family; The VHS domain is present in Vps27 (Vacuolar Protein Sorting), Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (Signal Transducing Adaptor Molecule). It has a superhelical structure similar to that of the ARM (Armadillo) repeats and is present at the N-termini of proteins involved in intracellular membrane trafficking. There are four general groups of VHS domain containing proteins based on their association with other domains. The first group consists of proteins of the STAM/EAST/Hbp family, which has the domain composition of VHS-SH3-ITAM. The second consists of proteins with a FYVE domain C-terminal to VHS. The third consists of GGA proteins with a domain composition of VHS-GAT (GGA and TOM)-GAE (Gamma-Adaptin Ear) domain. The fourth consists of proteins with a VHS domain alone or with domains other than those mentioned above. In GGA proteins, VHS domains are involved in cargo recognition in trans-Golgi, thereby having a general membrane targeting/cargo recognition role in vesicular trafficking.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377  29 LELWLNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFR 108
Cdd:cd03561    1 VEELVEKATSESLTEPDWALNLEICDLVNSDPAQAKDAVRALRKRLQSKNPKVQLLALTLLETLVKNCGAPFHSEVASRD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 213688377 109 FLNELIKVLSPKYLGawatEKVKGRVIEILFSWTVWFPEDIK---IRDAYQMLKK 160
Cdd:cd03561   81 FLQELVKLVKKKKTS----PEVREKALALIQEWAEAFQGDGRlplFYDTYQQLRR 131

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377 232 RRVSAVEEVRSHVRVLREMLSMYRrPGHALPDQQAL-QVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQGVL 310
Cdd:cd14234    1 KRLLELEEVNNNVKLLNEMLDHYS-PGESSQDELELmKELYESCEKMRPTLFRLASETDDDDEGLADILQANDELTRVMQ 79

                 ....*
gi 213688377 311 LYKQV 315
Cdd:cd14234   80 RYKNL 84

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).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 213688377 232 RRVSAVEEVRSHVRVLREMLSMYRRPGHALPDQQALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQGVLL 311
Cdd:cd14240    1 KRLHTLEEVNNNVRLLNEMLAHYSKEDSSDGDKELMKELYDRCEKKRRTLFKLASETEDNDNSLGDILQASDDLSRVINS 80

                 ....*..
gi 213688377 312 YKQVVEG 318
Cdd:cd14240   81 YKKIVEG 87

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 213688377  33 LNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFRFLNE 112
Cdd:cd03569    7 LDKATSQLLLEPDWESILQICDLIRQGDVTPKYAVSAIKKKLNDQNPHVALYALQVLESVVKNCGTPVHDEVATKEFMEE 86

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 213688377 113 LIKVLSPKylgawATEKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 162
Cdd:cd03569   87 LRDLVKTT-----TSENVRNKILELIQAWAHAFrnePKYKIVQDTYNIMKMEG 134

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 213688377  33 LNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQE-REALYALTVLEICMNHCGEKFHNEVAKFRFLN 111
Cdd:cd16996    6 IEKATDGSLQSEDWTLNMEICDIINETEEGPKDAIRALKKRLNGNKNyREVMLALTVLETCVKNCGHRFHVLVASRDFID 85

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 213688377 112 E-LIKVLSPKylgAWATEKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 162
Cdd:cd16996   86 GvLVKIISPK---NNPPTIVQDKVLALIQAWADAFrssPDLTGVVHIYEELKRKG 137

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 213688377  35 KATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKFRFLNELI 114
Cdd:cd16999    7 KATNEYNTSEDWSLIMDICDKVGSTPNGAKDCLKAIMKRVNHKVPHVALQALTLLGACVSNCGKIFHLEVCSRDFATEVR 86

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|..
gi 213688377 115 KVLSPKYLGAwATEKVKGRVIEilfsWTVWFPEDIK---IRDAYQMLKKQGI 163
Cdd:cd16999   87 AVIKNKAHPK-VCEKLKALMVE----WSEEFQKDPQfslISATIKSLKEEGI 133

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 213688377  33 LNKATNPSMAEQDWSAIQKFCEQVNTDPSGPTHAPWLLAHKIQSPQE-REALYALTVLEICMNHCGEKFHNEVAKFRFL- 110
Cdd:cd16995    6 IEKATDGSLQSEDWGLNMEICDIINETEEGPKDAIRAIKKRIVGNKNfREVMLALTVLETCVKNCGHRFHVLVASQDFVe 85

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*
gi 213688377 111 NELIKVLSPKylgAWATEKVKGRVIEILFSWTVWF---PEDIKIRDAYQMLKKQG 162
Cdd:cd16995   86 GVLVKTILPK---NNPPAIVHDKVLNLIQAWADAFrssPDLTGVVTVYEDLRRKG 137

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 213688377  29 LELWLNKATNPSMAEQDWSAIQKFCEQVN-TDPSGPTHAPWLLAHKIQSPQEREALYALTVLEICMNHCGEKFHNEVAKF 107
Cdd:cd16998    1 LQRYIERACDPSLEEPNLALNLEIADLINeKQGNTPREAAFAIVRLVNSRNPTVALLALHLLDVCVKNCGYPFHLQIASK 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 213688377 108 RFLNELIKVL---SPKYLGawateKVKGRVIEILFSWTV------WFPEDIK-IRDAYQMLK 159
Cdd:cd16998   81 EFLNELVRRFperPPSRLN-----PVQHKILELIEEWKQtlcktsRYKEDLGhIRDMHRLLS 137

canonical GAT domain found in metazoan and fungal ADP-ribosylation factor (Arf)-binding proteins (GGAs); GGAs, also called Golgi-localized gamma-ear-containing Arf-binding proteins, belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. GGAs also play important roles in ubiquitin-dependent sorting of cargo proteins both in biosynthetic and endocytic pathways. The family includes three GGAs (GGA1, GGA2, and GGA3) identified in mammals and two GGAs (Gga1p and Gga2p) identified in the budding yeast Saccharomyces cerevisiae. All these GGAs have a multidomain structure consisting of: an N-terminal VHS (Vps27/Hrs/Stam) domain that binds acidic-cluster dileucine (DxxLL)-type sorting signals (where x is any amino acid) found in the cytoplasmic tail of TGN sorting receptors; a GAT (GGA and TOM) domain that interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and the tumor susceptibility gene 101 product (TSG101); a largely unstructured hinge region that contains clathrin-binding motifs; and a C-terminal GAE (gamma-adaptin ear homology) domain that binds accessory proteins. In contrast to other GGAs-like proteins, members of this family contain a GAT N-terminal region, a helix-loop-helix in the complex with Arf1-GTP.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 213688377 237 VEEVRSHVRVLREMLSMYRRPGHALPDQQALQVVYERCEKLRPTLFRLASDTTDDDDALAEILQANDLLTQGVLLYK 313
Cdd:cd14230    2 LEEAKNNVDLLDEMLLSYSQEDSSDGDNELMKELYDQLENMRPTLFKLASETEENDNSLGDVLQASDNVNRVINKYK 78

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 213688377 238 EEVRSHVRVLREMLSMYrrPGHALPDQQALQVVYERCEKLRPTLFRLASDTTDDDD--ALAEILQANDLLTQGVLLYKQ 314
Cdd:cd21383    3 EEVKENASLLNEMLSAA--SPEELLDNELLQELVEFCRACQPRIVELIEATTDGLDedTLEELLELNDELNEALQRYDD 79

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 213688377 238 EEVRSHVRVLREMLSMYRRPGHALPDQQALQVVYERCEKLRPTLFRLASDTTDDDDaLAEILQANDLLTQGVLLYKQV 315
Cdd:cd12930    1 EEVKDNVR*FSELLEK*KSRPLEILDDELLQELAQRCFASKARLNYLLNDKADDQK-YNTLLE*NDNLSEV*NIYDRL 77