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 966969313   9 TLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 88
Cdd:cd17009    1 TLEARINRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 966969313  89 RFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 147
Cdd:cd17009   81 RFLNELIKVVSPKYLGSRTPEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 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 966969313   517 VYDQHGFRVLFHFARdplpgRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNPivhpsaITQVL 596
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 966969313   597 LLANPQKEKVRLRYKLTFTMGDQTYNEMGDVDQFP 631
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

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 966969313   9 TLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 88
Cdd:cd17009    1 TLEARINRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 966969313  89 RFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 147
Cdd:cd17009   81 RFLNELIKVVSPKYLGSRTPEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 139

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313    9 TLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 88
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRINSPNPHVALLALTLLDACVKNCGSKFHLEIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 966969313   89 RFLNELIKVVSPKYLGSRTseKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQG 143
Cdd:pfam00790  81 EFLNELVKLIPNKPYGKPA--KVKKKILELIQEWADAFkndPDLKYIRDMYKLLKRKG 136

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 966969313   517 VYDQHGFRVLFHFARdplpgRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNPivhpsaITQVL 596
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 966969313   597 LLANPQKEKVRLRYKLTFTMGDQTYNEMGDVDQFP 631
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 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 966969313  514 PVTVYDQHGFRVLFHFARDplpGRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNpivhPSAIT 593
Cdd:pfam02883   2 PVVLYESDGLQIGFSFERS---RRPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNP----GGQIT 74

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 966969313  594 QVLLLANPQKEKVRLRYKLTFTMGdQTYNEMGDVDQFP 631
Cdd:pfam02883  75 QVLLIENPGKKPLRMRLKISYLNG-GAVQEQGDVLKFP 111

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 966969313   9 TLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 88
Cdd:cd17009    1 TLEARINRATNPLNKELDWASINGFCEQLNEEFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 966969313  89 RFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 147
Cdd:cd17009   81 RFLNELIKVVSPKYLGSRTPEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 139

VHS (Vps27/Hrs/STAM) domain of ADP-ribosylation factor-binding protein GGA3; ADP-ribosylation factor-binding protein GGA3 (Golgi-localized, Gamma-ear-containing, Arf-binding 3) regulates the trafficking and is required for the lysosomal degradation of BACE (beta-site APP-cleaving enzyme), the protease that initiates the production of beta-amyloid, which causes Alzheimer's disease. It also plays a key role in GABA (+) transmission, which is important in the regulation of anxiety-like behaviors. GGA3 is a member of the GGA subfamily, which is comprised of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313   8 ETLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGK 87
Cdd:cd17008    2 ESLESWLNKATNPSNRQEDWEYIIGFCDQINKELEGPQIAVRLLAHKIQSPQEWEALQALTVLEACMKNCGRRFHNEVGK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313  88 FRFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVKS 147
Cdd:cd17008   82 FRFLNELIKVVSPKYLGDRVSEKVKTKVIELLYSWTVALPEEAKIKDAYHMLKRQGIVQS 141

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 966969313   9 TLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 88
Cdd:cd17010    1 SLESWLNKATDPSNSEEDWECIQGFCEQVNKEPEGPQIATRLLAHKIQSPQEREALHALTVLEMCMNNCGERFHSEVAKF 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*...
gi 966969313  89 RFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVK 146
Cdd:cd17010   81 RFLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIK 138

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313    9 TLEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKF 88
Cdd:pfam00790   1 PLERWIDKATDPSLREEDWSLILDICDLINETETGPKEAVRLIKKRINSPNPHVALLALTLLDACVKNCGSKFHLEIASK 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 966969313   89 RFLNELIKVVSPKYLGSRTseKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQG 143
Cdd:pfam00790  81 EFLNELVKLIPNKPYGKPA--KVKKKILELIQEWADAFkndPDLKYIRDMYKLLKRKG 136

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 966969313 213 KRVNAIEEVNNNVKLLTEMVMSHSQGGTAAGSSEdLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQVIN 292
Cdd:cd14234    1 KRLLELEEVNNNVKLLNEMLDHYSPGESSQDELE-LMKELYESCEKMRPTLFRLASETDDDDEGLADILQANDELTRVMQ 79

                 ....*
gi 966969313 293 LYKQL 297
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 966969313 213 KRVNAIEEVNNNVKLLTEMVMSHSQGGTAAGSSEdLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQVIN 292
Cdd:cd14240    1 KRLHTLEEVNNNVRLLNEMLAHYSKEDSSDGDKE-LMKELYDRCEKKRRTLFKLASETEDNDNSLGDILQASDDLSRVIN 79

                 ....*...
gi 966969313 293 LYKQLVRG 300
Cdd:cd14240   80 SYKKIVEG 87

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 966969313   517 VYDQHGFRVLFHFARdplpgRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNPivhpsaITQVL 596
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 966969313   597 LLANPQKEKVRLRYKLTFTMGDQTYNEMGDVDQFP 631
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 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 966969313  514 PVTVYDQHGFRVLFHFARDplpGRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNpivhPSAIT 593
Cdd:pfam02883   2 PVVLYESDGLQIGFSFERS---RRPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNP----GGQIT 74

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 966969313  594 QVLLLANPQKEKVRLRYKLTFTMGdQTYNEMGDVDQFP 631
Cdd:pfam02883  75 QVLLIENPGKKPLRMRLKISYLNG-GAVQEQGDVLKFP 111

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 966969313 218 IEEVNNNVKLLTEMVMSHSQGGTAAGSSEdLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQVINLYKQL 297
Cdd:cd14230    2 LEEAKNNVDLLDEMLLSYSQEDSSDGDNE-LMKELYDQLENMRPTLFKLASETEENDNSLGDVLQASDNVNRVINKYKDI 80

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 966969313  169 FEDEEKSKMLARLLKSSHPEDLRAANKLIKEMVQEDQKR 207
Cdd:pfam18308   1 FDDEEKSKLLARLLKSKNPEDLQAANRLIKSMVKEDDER 39

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 966969313  13 RINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEW-EAIQALTVLETCMKSCGKRFHDEVGKFRFL 91
Cdd:cd16995    5 RIEKATDGSLQSEDWGLNMEICDIINETEEGPKDAIRAIKKRIVGNKNFrEVMLALTVLETCVKNCGHRFHVLVASQDFV 84

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 966969313  92 -NELIKVVSPKylgSRTSEKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQG 143
Cdd:cd16995   85 eGVLVKTILPK---NNPPAIVHDKVLNLIQAWADAFrssPDLTGVVTVYEDLRRKG 137

GAT domain found in eukaryotic GGAs, metazoan Tom1-like proteins, metazoan STAMs, fungal Vps27, and similar proteins; The GAT (GGA and Tom1) domain superfamily includes the canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins (GGAs) from eukaryotes, myb protein 1 (Tom1)-like proteins from metazoa, and LAS seventeen-binding protein 5 (Lsb5p)-like proteins from fungi. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin. GGAs, also called Golgi-localized gamma-ear-containing Arf-binding proteins, belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. GGAs play important roles in ubiquitin-dependent sorting of cargo proteins both in biosynthetic and endocytic pathways. Tom1 and its related proteins, Tom1L1 and Tom1L2, form a protein family sharing an N-terminal VHS-domain followed by a GAT domain. Tom1 family proteins bind to ubiquitin, ubiquitinated proteins, and Toll-interacting protein (Tollip) through its GAT domain. They do not associate with either Arf GTPases through its GAT domain nor with acidic cluster-dileucine sequences through its VHS domain. The GAT domain superfamily also includes the non-canonical GAT domain found in several components of the ESCRT-0 complex, including signal transducing adapter molecules (STAMs) and hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) from metazoa, as well as vacuolar protein sorting-associated protein 27 (Vps27) and class E vacuolar protein-sorting machinery protein Hse1 from fungi. Hrs, together with STAM, forms a Hrs/STAM core complex. Vps27, together with Hse1, forms a Vps27/Hse1 core complex. Those complexes consist of two intertwined GAT domains, each consisting of two helices from one subunit, and one from the other subunit. The intertwined GAT heterodimer acts as a scaffold for binding of ubiquitinated cargo proteins and coordinating ubiquitination and deubiquitination reactions that regulate sorting.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 966969313 219 EEVNNNVKLLTEMVMSHSQGGTAAGSSEdLMKELYQRCERMRPTLFRLASDTEDnDEALAEILQANDNLTQVINLYKQL 297
Cdd:cd12930    1 EEVKDNVR*FSELLEK*KSRPLEILDDE-LLQELAQRCFASKARLNYLLNDKAD-DQKYNTLLE*NDNLSEV*NIYDRL 77

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 966969313  10 LEARINRATNPLNKELDWASINGFCEQLNEDFEGPP------LATRlLAHK---IQspqeweaIQALTVLETCMKSCGKR 80
Cdd:cd16978    1 IDELIIKATDETLTSENWQYILDVCDKVNSDPEDGAreaiaaIQKR-LQHRnanVQ-------LRSLSLADALAKNCGSR 72

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313  81 FHDEVGKFRFLNELIKVVspkyLGSRTSEKVKNKILELLYSWTvglpEEVK-------IAEAYQMLKKQG 143
Cdd:cd16978   73 LHQEISSRSFTQTLLRLI----NDRTTHATVKKRILELIKQLS----DSFKsdpslglMSDTYDQLKSKY 134

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 966969313  10 LEARINRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKFR 89
Cdd:cd16999    1 FEQDVEKATNEYNTSEDWSLIMDICDKVGSTPNGAKDCLKAIMKRVNHKVPHVALQALTLLGACVSNCGKIFHLEVCSRD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*....
gi 966969313  90 FLNELIKVVSPKylgsrTSEKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQGIV 145
Cdd:cd16999   81 FATEVRAVIKNK-----AHPKVCEKLKALMVEWSEEFqkdPQFSLISATIKSLKEEGIT 134

VHS (Vps27/Hrs/STAM) domain of Signal Transducing Adapter Molecule 1; Signal Transducing Adapter Molecule 1 (STAM1) is part of a crucial regulatory axis for the ventral axonal trajectory of developing spinal motor neurons. It forms a complex with beta-arrestin, which regulates lysosomal trafficking of the chemokine receptor CXCR4 and also mediates CXCR4-dependent chemotaxis. STAM (Signal Transducing Adaptor Molecule) subfamily members have at their N-termini a VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats, followed by a Ubiquitin-Interacting Motif (UIM) and a SH3 (Src Homology 3) domain, which is a well-established protein-protein interaction domain, and a GAT (GGA and TOM) domain. At the C-termini of most vertebrate STAMS, an Immunoreceptor Tyrosine-based Activation Motif (ITAM) is present, which mediates the binding of HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in endocytic and exocytic machineries. STAM is a component of the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery and together with Hrs, functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313  14 INRATNPLNKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGKFRFLNE 93
Cdd:cd17000    5 VEKATSEMNTAEDWGLILDICDKVGQSRTGPKDCLRSIMRRVNHKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDFASE 84

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 966969313  94 LIKVVspkylgSRTSEKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQG 143
Cdd:cd17000   85 VSNVL------NKGHPKVCEKLKALMVEWTEEFkndPQLSLISAMIKNLKEQG 131

VHS (Vps27/Hrs/STAM) domain of Vacuolar protein sorting-associated protein 27; Vacuolar protein sorting-associated protein 27 (Vps27 or Vps27p) is also called Golgi retention defective protein 11, and is the yeast homolog of Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate). Together with class E vacuolar protein-sorting machinery protein HSE1, it comprises the ESCRT-0 complex, the sorting receptor for ubiquitinated cargo proteins at the multivesicular body (MVB). The complex directly binds to ubiquitinated transmembrane proteins and recruits both ubiquitin ligases and deubiquitinating enzymes. It is also required the efficient recycling of late Golgi proteins including the carboxypeptidase Y (CPY) sorting receptor, Vps10. Vps27 contain similar domains and motifs to Hrs; it contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, two Ubiquitin-Interacting Motifs (UIMs), a GAT (GGA and TOM) domain, two a P(S/T)XP motifs that recruit ESCRT-I, and a short peptide motif near the C-terminus that recruits clathrin.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313  10 LEARINRATNPL--NKELDWASINGFCEQLNEDFEGPPLATRLLAHKIQSPQEWEAIQALTVLETCMKSCGKRFHDEVGK 87
Cdd:cd16979    3 FDELIEKATSESipNGEEDLALALEISDLIRSKSVPPKDAMRSLKKRILHKNPNVQLLALKLTDVCVKNGGDHFLVEIAS 82

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313  88 FRFLNELIKVVspkyLGSRTSEKVKNKILELLYSWTV---GLPEEVKIAEAYQMLKKQGI 144
Cdd:cd16979   83 REFMDNLVSLI----RSTGVNPEVKEKILRLIQEWALafkSKSQLSYVVEVYKKLKSEGI 138

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966969313 209 EKISKRVNAIEEVNNNVKLLTEMVMSHSQGGTAAgSSEDLMKELYQRCERMRPTLFRLASDTEdNDEALAEILQANDNLT 288
Cdd:cd14238    2 EQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDP-SDLELLQELNRTCRAMQQRIVELISRVS-NEEVTEELLHVNDDLN 79

                         90
                 ....*....|.
gi 966969313 289 QVINLYKQLVR 299
Cdd:cd14238   80 NVFLRYERFER 90

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

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 966969313 221 VNNNVKLLTEMvMSHSQGGTAAGSSEDLMKELYQRCERMRPTLFRLASdTEDNDEALAEILQANDNLTQVINLYKQLVR 299
Cdd:cd14233   11 VEGNLKVMSEM-LTELVPGQENPDDLELLQELNSTCRAMQQRVVELIS-QVSNEEVTEELLRVNDDLNNVFLRYERFER 87

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 966969313 209 EKISKRVNAIEEVNNNVKLLTEMvMSHSQGGTAAGSSEDLMKELYQRCERMRPTLFRLASDTEdNDEALAEILQANDNLT 288
Cdd:cd14236    2 EQIGKLRSELEMVSGNVRVMSEM-LTELVPTQAEPADLELLQELNRTCRAMQQRVLELIPQIA-NEQLTEELLIVNDNLN 79

                 ..
gi 966969313 289 QV 290
Cdd:cd14236   80 NV 81