canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins GGA1 and GGA2; This subfamily includes GGA1 and GGA2, both of which belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. GGA1, also called gamma-adaptin-related protein 1, or Golgi-localized gamma ear-containing Arf-binding protein 1, regulates the low-density lipoprotein and sorting receptor LR11/SorLA endocytic traffic and further alters amyloid-beta precursor protein (APP) intracellular distribution and amyloid-beta production. It is also critical for the effects of beta-site APP-cleaving enzyme-1 (BACE1) on amyloid-beta generation. It interacts with BACE1 and promotes its traffic from early endosomes to late endocytic compartments or the TGN. Moreover, GGA1 acts as a clathrin assembly protein with the ability to polymerize clathrin into tubules. GGA2, also called gamma-adaptin-related protein 2, Golgi-localized gamma ear-containing Arf-binding protein 2, or VHS domain and ear domain of gamma-adaptin (Vear), interacts with the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR) and further plays a major role in the sorting of lysosomal enzymes. It also mediates a vital function that cannot be compensated for by GGA1 and/or GGA3. Both GGA1 and GGA2 have a multidomain structure consisting of an N-terminal VHS (Vps27/Hrs/Stam) domain, a GAT (GGA and TOM) domain, a largely unstructured hinge region that contains clathrin-binding motifs, and a C-terminal GAE (gamma-adaptin ear homology) domain. The GAT domain of GGAs interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and/or the tumor susceptibility gene 101 product (TSG101).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217339544 137 KISKRVNAIEEVNNNVKLLTEMVMSHSQGGAAaGSSEDLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQ 216
Cdd:cd14239     1 KVSKRVNAIEEVNNNVKLLTEMLMSYSRGELS-ESSEELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNLTQ 79

                  ....*....
gi 2217339544 217 VINLYKQLV 225
Cdd:cd14239    80 VINLYKQLV 88

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 2217339544  444 VYDQHGFRILFHFARdplpgRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNPivhpsaITQVL 523
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 2217339544  524 LLANPQKEKVRLRYKLTFTMGDQTYNEMGDVDQFP 558
Cdd:smart00809  70 KVENPGKFPLRLRLRLSYLLGGSAVTEQGDVLKFP 104

canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins GGA1 and GGA2; This subfamily includes GGA1 and GGA2, both of which belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. GGA1, also called gamma-adaptin-related protein 1, or Golgi-localized gamma ear-containing Arf-binding protein 1, regulates the low-density lipoprotein and sorting receptor LR11/SorLA endocytic traffic and further alters amyloid-beta precursor protein (APP) intracellular distribution and amyloid-beta production. It is also critical for the effects of beta-site APP-cleaving enzyme-1 (BACE1) on amyloid-beta generation. It interacts with BACE1 and promotes its traffic from early endosomes to late endocytic compartments or the TGN. Moreover, GGA1 acts as a clathrin assembly protein with the ability to polymerize clathrin into tubules. GGA2, also called gamma-adaptin-related protein 2, Golgi-localized gamma ear-containing Arf-binding protein 2, or VHS domain and ear domain of gamma-adaptin (Vear), interacts with the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR) and further plays a major role in the sorting of lysosomal enzymes. It also mediates a vital function that cannot be compensated for by GGA1 and/or GGA3. Both GGA1 and GGA2 have a multidomain structure consisting of an N-terminal VHS (Vps27/Hrs/Stam) domain, a GAT (GGA and TOM) domain, a largely unstructured hinge region that contains clathrin-binding motifs, and a C-terminal GAE (gamma-adaptin ear homology) domain. The GAT domain of GGAs interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and/or the tumor susceptibility gene 101 product (TSG101).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217339544 137 KISKRVNAIEEVNNNVKLLTEMVMSHSQGGAAaGSSEDLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQ 216
Cdd:cd14239     1 KVSKRVNAIEEVNNNVKLLTEMLMSYSRGELS-ESSEELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNLTQ 79

                  ....*....
gi 2217339544 217 VINLYKQLV 225
Cdd:cd14239    80 VINLYKQLV 88

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 2217339544  444 VYDQHGFRILFHFARdplpgRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNPivhpsaITQVL 523
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 2217339544  524 LLANPQKEKVRLRYKLTFTMGDQTYNEMGDVDQFP 558
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 2217339544 441 PVTVYDQHGFRILFHFARDplpGRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNpivhPSAIT 520
Cdd:pfam02883   2 PVVLYESDGLQIGFSFERS---RRPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNP----GGQIT 74

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2217339544 521 QVLLLANPQKEKVRLRYKLTFTMGdQTYNEMGDVDQFP 558
Cdd:pfam02883  75 QVLLIENPGKKPLRMRLKISYLNG-GAVQEQGDVLKFP 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 2217339544  96 FEDEEKSKMLARLLKSSHPEDLRAANKLIKEMVQEDQKR 134
Cdd:pfam18308   1 FDDEEKSKLLARLLKSKNPEDLQAANRLIKSMVKEDDER 39

canonical GAT domain found in ADP-ribosylation factor (Arf)-binding proteins GGA1 and GGA2; This subfamily includes GGA1 and GGA2, both of which belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. GGA1, also called gamma-adaptin-related protein 1, or Golgi-localized gamma ear-containing Arf-binding protein 1, regulates the low-density lipoprotein and sorting receptor LR11/SorLA endocytic traffic and further alters amyloid-beta precursor protein (APP) intracellular distribution and amyloid-beta production. It is also critical for the effects of beta-site APP-cleaving enzyme-1 (BACE1) on amyloid-beta generation. It interacts with BACE1 and promotes its traffic from early endosomes to late endocytic compartments or the TGN. Moreover, GGA1 acts as a clathrin assembly protein with the ability to polymerize clathrin into tubules. GGA2, also called gamma-adaptin-related protein 2, Golgi-localized gamma ear-containing Arf-binding protein 2, or VHS domain and ear domain of gamma-adaptin (Vear), interacts with the acidic cluster-dileucine motif in the cytoplasmic tail of the cation-independent mannose 6-phosphate receptor (CI-MPR) and further plays a major role in the sorting of lysosomal enzymes. It also mediates a vital function that cannot be compensated for by GGA1 and/or GGA3. Both GGA1 and GGA2 have a multidomain structure consisting of an N-terminal VHS (Vps27/Hrs/Stam) domain, a GAT (GGA and TOM) domain, a largely unstructured hinge region that contains clathrin-binding motifs, and a C-terminal GAE (gamma-adaptin ear homology) domain. The GAT domain of GGAs interacts with class I GTP-bound form of Arf proteins, Rabaptin-5, ubiquitin, and/or the tumor susceptibility gene 101 product (TSG101).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2217339544 137 KISKRVNAIEEVNNNVKLLTEMVMSHSQGGAAaGSSEDLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQ 216
Cdd:cd14239     1 KVSKRVNAIEEVNNNVKLLTEMLMSYSRGELS-ESSEELMKELYQRCEKMRPTLFRLASDTEDNDEALAEILQANDNLTQ 79

                  ....*....
gi 2217339544 217 VINLYKQLV 225
Cdd:cd14239    80 VINLYKQLV 88

VHS (Vps27/Hrs/STAM) domain of metazoan GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) proteins; GGA (Golgi-localized, Gamma-ear-containing, Arf-binding) comprises a subfamily of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins involved in membrane trafficking between the Trans-Golgi Network (TGN) and endosomes. Jawed vertebrates contain as many as three GGA proteins: GGA1, GGA2, and GGA3. The VHS domain has a superhelical structure similar to the structure of the ARM (Armadillo) repeats and is present at the N-termini of proteins. GGA proteins have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain. The VHS domain of GGA proteins binds to the acidic-cluster dileucine (DxxLL) motif found on the cytoplasmic tails of cargo proteins trafficked between the Trans-Golgi Network and the endosomal system.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVK 73
Cdd:cd03567    66 VKNCGPRFHSEVGKFRFLNELIKLVSPKYLGNRTPEEVKQKIIELLYSWTRSLPHEPKIKEAYDMLKKQGIIK 138

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQGIVK 73
Cdd:cd17010    66 MNNCGERFHSEVAKFRFLNELIKVLSPKYLGTWSSEKVKSRVIEVLFSWTVWLPEEVKIRDAYQMLKKQGIIK 138

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWTVGLPEEVKIAEAYQMLKKQ 69
Cdd:cd16977    65 MKNCGYRFHLEVGKFRFLNELIKVVSPKYLGSRRSEKVKRKILELLYSWTVTLPEEGKIRDAYQMLKKQ 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 2217339544  444 VYDQHGFRILFHFARdplpgRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNPivhpsaITQVL 523
Cdd:smart00809   1 AYEKNGLQIGFKFER-----RPGLIRITLTFTNKSPSPITNFSFQAAVPKSLKLQLQPPSSPTLPPGGQ------ITQVL 69

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 2217339544  524 LLANPQKEKVRLRYKLTFTMGDQTYNEMGDVDQFP 558
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 2217339544 441 PVTVYDQHGFRILFHFARDplpGRSDVLVVVVSMLSTAPQPIRNIVFQSAVPKVMKVKLQPPSGTELPAFNpivhPSAIT 520
Cdd:pfam02883   2 PVVLYESDGLQIGFSFERS---RRPGQIRITLTFTNKSSSPISNFSFQAAVPKSLKLQLQPPSSNVLPPNP----GGQIT 74

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 2217339544 521 QVLLLANPQKEKVRLRYKLTFTMGdQTYNEMGDVDQFP 558
Cdd:pfam02883  75 QVLLIENPGKKPLRMRLKISYLNG-GAVQEQGDVLKFP 111

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

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNELIKVVSPKYLGSRTseKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQG 70
Cdd:pfam00790  66 VKNCGSKFHLEIASKEFLNELVKLIPNKPYGKPA--KVKKKILELIQEWADAFkndPDLKYIRDMYKLLKRKG 136

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 2217339544 146 EEVNNNVKLLTEMVMSHSQGGAAAGSSEdLMKELYQRCERMRPTLFRLASDTEdNDEALAEILQANDNLTQVINLYKQL 224
Cdd:cd12930     1 EEVKDNVR*FSELLEK*KSRPLEILDDE-LLQELAQRCFASKARLNYLLNDKA-DDQKYNTLLE*NDNLSEV*NIYDRL 77

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNELIKVVSPKylgsRTSEKVKNKILELLYSWTVGLPEEVK---IAEAYQMLKK 68
Cdd:cd03561    65 VKNCGAPFHSEVASRDFLQELVKLVKKK----KTSPEVREKALALIQEWAEAFQGDGRlplFYDTYQQLRR 131

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
                  ....*....|....*....|....*....|....*....|....*....|
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNELIKVVSPKYLGSRTSEKVKNKILELLYSWT 50
Cdd:cd00197    65 VKNCGERFHQEVASNDFAVELLKFDKSGLLGDDVSTNVREKAIELVQLWA 114

VHS (Vps27/Hrs/STAM) domain of Tom1 subfamily; This subfamily is composed of Tom1 (Target of myb1 - retroviral oncogene) protein, Tom1L1 (Tom1-like1), Tom1L2 (Tom1-like2), and similar proteins. Proteins belonging to this subfamily are characterized by the presence of a VHS (Vps27p/Hrs/Stam) domain in the N-terminal portion followed by a GAT (GGA and Tom) domain. They are novel regulators for post-Golgi trafficking and signaling. Yeast do not contain homologous proteins of the Tom1 subfamily, suggesting these proteins have evolved to accommodate more complex cellular processes. Tom1 is essential for the negative regulation of Interleukin-1 and Tumor Necrosis Factor-induced signaling pathways. The VHS domain has a superhelical structure similar to the structure of the ARM repeats and is present at the very N-termini of proteins. It is a right-handed superhelix of eight alpha helices. The VHS domain has been found in a number of proteins, some of which have been implicated in intracellular trafficking and sorting.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 2217339544   2 KSCGKRFHDEVGKFRFLNELIKVVSPKYlgsRTSEKVKNKILELLYSWT---VGLPEEVKIAEAYQMLKKQG 70
Cdd:cd03565    70 KNCGHRFHVLVANKDFLQELVKLIGPKN---DPPTIVQEKVLSLIQSWAdafRGQPDLQEVVKVYQELKAKG 138

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 2217339544 139 SKRVNA-IEEVNNNVKLLTEMVMSHSQGgaAAGSSEDLMKELYQRCERMRPTLFRLASDTEDNDEALAEILQANDNLTQV 217
Cdd:cd14235     3 KAQVAEeLEKLKRKAILLNEMLNNATPG--EIDVEGDTYDELASSLKSAQPKIQKIIEEESEDEESVQKLLELNDLINSL 80

                          90
                  ....*....|
gi 2217339544 218 INLYKQLVRG 227
Cdd:cd14235    81 LERYDLLKKG 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2217339544 148 VNNNVKLLTEMVMSHSQGGAAAGSSEdLMKELYQRCERMRPTLFRLASdTEDNDEALAEILQANDNLTQVINLYKQLVR 226
Cdd:cd14233    11 VEGNLKVMSEMLTELVPGQENPDDLE-LLQELNSTCRAMQQRVVELIS-QVSNEEVTEELLRVNDDLNNVFLRYERFER 87

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 2217339544   2 KSCGKRFHDEVGKFRFLNELIKVVspkyLGSRTSEKVKNKILELLYSWTvglpEEVK-------IAEAYQMLKKQG 70
Cdd:cd16978    67 KNCGSRLHQEISSRSFTQTLLRLI----NDRTTHATVKKRILELIKQLS----DSFKsdpslglMSDTYDQLKSKY 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 2217339544   1 MKSCGKRFHDEVGKFRFLNE-LIKVVSPKylgSRTSEKVKNKILELLYSWTVGL---PEEVKIAEAYQMLKKQG 70
Cdd:cd16996    67 VKNCGHRFHVLVASRDFIDGvLVKIISPK---NNPPTIVQDKVLALIQAWADAFrssPDLTGVVHIYEELKRKG 137

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 2217339544 136 EKISKRVNAIEEVNNNVKLLTEMvMSHSQGGAAAGSSEDLMKELYQRCERMRPTLFRLASDTEdNDEALAEILQANDNLT 215
Cdd:cd14236     2 EQIGKLRSELEMVSGNVRVMSEM-LTELVPTQAEPADLELLQELNRTCRAMQQRVLELIPQIA-NEQLTEELLIVNDNLN 79

                          90
                  ....*....|.
gi 2217339544 216 QVINLYKQLVR 226
Cdd:cd14236    80 NVFLRHERFER 90