VHS, ENTH and ANTH domain superfamily; This superfamily is composed of proteins containing a VHS, CID, ENTH, or ANTH domain. The VHS domain is present in Vps27 (Vacuolar Protein Sorting), Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (Signal Transducing Adaptor Molecule). It is located at the N-termini of proteins involved in intracellular membrane trafficking. The CTD-Interacting Domain (CID) is present in several RNA-processing factors and binds tightly to the carboxy-terminal domain (CTD) of RNA polymerase II (RNAP II or Pol II). The epsin N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated endocytosis. A set of proteins previously designated as harboring an ENTH domain in fact contains a highly similar, yet unique module referred to as an AP180 N-Terminal Homology (ANTH) domain. VHS, ENTH, and ANTH domains are structurally similar and are composed of a superhelix of eight alpha helices. ENTH and ANTH (E/ANTH) domains bind both inositol phospholipids and proteins and contribute to the nucleation and formation of clathrin coats on membranes. ENTH domains also function in the development of membrane curvature through lipid remodeling during the formation of clathrin-coated vesicles. E/ANTH domain-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the Trans-Golgi Network, which suggests that E/ANTH domains are universal components of the machinery for clathrin-mediated membrane budding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSGNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSVLVKIISPKNNPPTIV 80
Cdd:cd16996    23 MEICDIINETEEGPKDAIRALKKRLNGNKNYREVMLALTVLETCVKNCGHRFHVLVASRDFIDGVLVKIISPKNNPPTIV 102

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1720365268  81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRG 115
Cdd:cd16996   103 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 137

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 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSGNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSVLVKIISPKNNPPTIV 80
Cdd:cd16996    23 MEICDIINETEEGPKDAIRALKKRLNGNKNYREVMLALTVLETCVKNCGHRFHVLVASRDFIDGVLVKIISPKNNPPTIV 102

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1720365268  81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRG 115
Cdd:cd16996   103 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 137

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268    1 MEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSvLVKIISPKNNPPTiV 80
Cdd:smart00288  22 LEICDLINSTPDGPKDAVRLLKKRLN-NKNPHVALLALTLLDACVKNCGSKFHLEVASKEFLNE-LVKLIKPKYPLPL-V 98

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1720365268   81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRG 115
Cdd:smart00288  99 KKRILELIQEWADAFKNDPDLSQIVDVYDLLKKKG 133

GAT domain; The GAT domain is responsible for binding of GGA proteins to several members of the ARF family including ARF1 and ARF3. The GAT domain stabilizes membrane bound ARF1 in its GTP bound state, by interfering with GAP proteins.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1720365268 199 RGNTKVMSEMLTEMVPGQEDssDLELLQELNRTCRAMQHRIVELISRVSNEE-VTEELLHVNDDLNNVFLRYERFER 274
Cdd:pfam03127   1 RNNAKLLNEMLSSTDPDEEL--DNELIKELYERCKSAQPKIQKLIEETSDEDdLLAELLQLNDDLNNVLERYERLKK 75

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 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSGNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSVLVKIISPKNNPPTIV 80
Cdd:cd16996    23 MEICDIINETEEGPKDAIRALKKRLNGNKNYREVMLALTVLETCVKNCGHRFHVLVASRDFIDGVLVKIISPKNNPPTIV 102

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 1720365268  81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRG 115
Cdd:cd16996   103 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRKG 137

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSGN--RNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSvLVKIISPKNNPPT 78
Cdd:cd03565    23 MEICDMINETDDGPKDAIKAIKKRLSTNagKNHTVVMYTLTLLETCVKNCGHRFHVLVANKDFLQE-LVKLIGPKNDPPT 101

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1720365268  79 IVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRG 115
Cdd:cd03565   102 IVQEKVLSLIQSWADAFRGQPDLQEVVKVYQELKAKG 138

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268 188 IARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNNVFL 267
Cdd:cd14233     1 IAKLRSELDVVEGNLKVMSEMLTELVPGQENPDDLELLQELNSTCRAMQQRVVELISQVSNEEVTEELLRVNDDLNNVFL 80

                  ....*..
gi 1720365268 268 RYERFER 274
Cdd:cd14233    81 RYERFER 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 1720365268 185 SEQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNN 264
Cdd:cd14236     1 PEQIGKLRSELEMVSGNVRVMSEMLTELVPTQAEPADLELLQELNRTCRAMQQRVLELIPQIANEQLTEELLIVNDNLNN 80

                          90
                  ....*....|....*
gi 1720365268 265 VFLRYERFERYRSGR 279
Cdd:cd14236    81 VFLRHERFERFRTGQ 95

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 1720365268   1 MEICDIINETEEGPKDAIRALKKRLsGNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSvLVKIISPKNNPPTiV 80
Cdd:cd03561    22 LEICDLVNSDPAQAKDAVRALRKRL-QSKNPKVQLLALTLLETLVKNCGAPFHSEVASRDFLQE-LVKLVKKKKTSPE-V 98

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1720365268  81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKR 113
Cdd:cd03561    99 REKALALIQEWAEAFQGDGRLPLFYDTYQQLRR 131

canonical GAT domain found in target of Myb-like protein 1 (Tom1L1); Tom1L1, also called Src-activating and signaling molecule protein (Srcasm), was identified as a substrate of the Src family of protein kinases. It is tyrosine-phosphorylated by Src family kinases and modulates growth factor and Src-mediated signaling pathways. It also plays a potential role in endosomal sorting and ligand-stimulated endocytosis of EGF receptors (EGFR). Tom1L1 is predominantly present in the cytosol and can interact with Toll-interacting protein (Tollip), Hrs or TSG101, clathrin, and ubiquitinated proteins. It 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 1720365268 186 EQIARLRSELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNNV 265
Cdd:cd14237     2 EQIGKLYSELDIVKMNVRVMSAILLENTPGAENPEDMELLEKLYKTCREMQERIMKLLETVENEDVIIELIQVNDDLNNV 81

                          90
                  ....*....|.
gi 1720365268 266 FLRYERFERYR 276
Cdd:cd14237    82 FLRHERFSRNR 92

VHS (Vps27/Hrs/STAM) domain of Hepatocyte growth factor-regulated tyrosine kinase substrate, Hrs; Hrs (Hepatocyte growth factor-regulated tyrosine kinase substrate) plays a role in at least three vesicle trafficking events: exocytosis, endocytosis, and endosome to lysosome trafficking. Hrs is involved in promoting rapid recycling of endocytosed signaling receptors to the plasma membrane. Together with STAM or STAM2, it comprises the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery, which functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Hrs contains an N-terminal VHS domain, which has a superhelical structure similar to the structure of ARM (Armadillo) repeats, a FYVE (Fab1p, YOTB, Vac1p, and EEA1) zinc finger domain, a Double Ubiquitin-Interacting Motif (DUIM), a P(S/T)XP motif that recruit ESCRT-I, a GAT (GGA and TOM) domain, and a short peptide motif near the C-terminus that recruits clathrin.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSV--LVKIISPKNnppt 78
Cdd:cd03569    24 LQICDLIRQGDVTPKYAVSAIKKKLN-DQNPHVALYALQVLESVVKNCGTPVHDEVATKEFMEELrdLVKTTTSEN---- 98

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1720365268  79 iVQDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRGIEFP 119
Cdd:cd03569    99 -VRNKILELIQAWAHAFRNEPKYKIVQDTYNIMKMEGYKFP 138

VHS (Vps27/Hrs/STAM) domain of the STAM (Signal Transducing Adaptor Molecule) subfamily; STAM (Signal Transducing Adaptor Molecule) subfamily members have at their N-termini a VHS domain, which is involved in cytokine-mediated intracellular signal transduction and has a superhelical structure similar to the structure of ARM (Armadillo) repeats, followed by a Ubiquitin-Interacting Motif (UIM) and a SH3 (Src Homology 3) domain, which is a well-established protein-protein interaction domain, and a GAT (GGA and TOM) domain. At the C-termini of most vertebrate STAMs, an Immunoreceptor Tyrosine-based Activation Motif (ITAM) is present, which mediates the binding of HRS (hepatocyte growth factor-regulated tyrosine kinase substrate) in endocytic and exocytic machineries. STAM is a component of the ESCRT (Endosomal Sorting Complex Required for Transport)-0 machinery and together with Hrs, functions to bind and sequester cargoes for downstream sorting into intralumenal vesicles. Jawed vertebrates have two STAM subfamily members, STAM1 and STAM2.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268   1 MEICDIINETEEGPKDAIRALKKRLsGNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSVLVKIisPKNNPPtiV 80
Cdd:cd03568    22 LDICDKVGRSPNGAKDCLKSIMKRL-NHKDPHVALQALTLLDACVKNCGKIFHLEVCSRDFESELRKLL--TKSHPK--V 96

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1720365268  81 QDKVLALIQAWADA-FRSSPDLTGVVHIYEELKRRG 115
Cdd:cd03568    97 AEKLKELLKKWAEEeFKDDPQLSLIPSLYKKLKAEG 132

VHS (Vps27/Hrs/STAM) domain of LAS seventeen-binding protein 5; LAS seventeen-binding protein 5 (LAS17-binding protein 5, Lsb5, or Lsb5p) localizes to the plasma membrane and plays a role in endocytosis in yeast. It interacts with actin regulators Sla1p and Las17p, ubiquitin, and Arf3p, coupling actin dynamics to membrane trafficking processes. Lsb5p contains an N-terminal VHS domain and a GAT (GGA and TOM) domain. The VHS domain has a superhelical structure similar to the structure of ARM (Armadillo) repeats. 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 1720365268   1 MEICDIINETEEGPKDAIRALKKRL-SGNRNyrEVMLALTVLETCVKNCGHRFHLLVANRDFIDsVLVKIISPKNNPPTI 79
Cdd:cd16980    22 LELCELINLIESGAKEAARALRKKLkYGNPH--QQLRALTLLDLLVENGGKKFQAQFASDKKLE-DLLRLIASDPSTDPK 98

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1720365268  80 VQDKVLALIQAWADAFRSSPDLTGVVHIYEELKR 113
Cdd:cd16980    99 VRKKLLELLGGWAYEFKGDPGLSGIASLYKKVKP 132

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 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSVLvKIISPKNNPPtiV 80
Cdd:cd16999    22 MDICDKVGSTPNGAKDCLKAIMKRVN-HKVPHVALQALTLLGACVSNCGKIFHLEVCSRDFATEVR-AVIKNKAHPK--V 97

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1720365268  81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRGIEFPMA 121
Cdd:cd16999    98 CEKLKALMVEWSEEFQKDPQFSLISATIKSLKEEGITFPPA 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        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720365268   3 ICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSvLVKIISPKnnPPTI--- 79
Cdd:cd16977    24 FCDQINEDGEGPRDAARLLAHKIQ-SPQEWEAIQALTVLEVCMKNCGYRFHLEVGKFRFLNE-LIKVVSPK--YLGSrrs 99

                          90       100       110
                  ....*....|....*....|....*....|....*..
gi 1720365268  80 --VQDKVLALIQAWADAFrssPDLTGVVHIYEELKRR 114
Cdd:cd16977   100 ekVKRKILELLYSWTVTL---PEEGKIRDAYQMLKKQ 133

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 1720365268   4 CDIINETEEGPKDAIRALKKRLSGNRNYrEVMLALTVLETCVKNCGHRFHLLVANRDFIDSvLVKIISPK---NNPPTIV 80
Cdd:cd17008    28 CDQINKELEGPQIAVRLLAHKIQSPQEW-EALQALTVLEACMKNCGRRFHNEVGKFRFLNE-LIKVVSPKylgDRVSEKV 105

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1720365268  81 QDKVLALIQAWADAFrssPDLTGVVHIYEELKRRGI 116
Cdd:cd17008   106 KTKVIELLYSWTVAL---PEEAKIKDAYHMLKRQGI 138

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 1720365268   1 MEICDIINETE-EGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSvLVKIIsPkNNPPTI 79
Cdd:cd16998    22 LEIADLINEKQgNTPREAAFAIVRLVN-SRNPTVALLALHLLDVCVKNCGYPFHLQIASKEFLNE-LVRRF-P-ERPPSR 97

                          90
                  ....*....|....*
gi 1720365268  80 ---VQDKVLALIQAW 91
Cdd:cd16998    98 lnpVQHKILELIEEW 112

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

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gi 1720365268   1 MEICDIINETEEGPKDAIRALKKRLSgNRNYREVMLALTVLETCVKNCGHRFHLLVANRDFIDSvlVKIISPKNNPPtiV 80
Cdd:cd17000    22 LDICDKVGQSRTGPKDCLRSIMRRVN-HKDPHVAMQALTLLGACVSNCGKIFHLEVCSRDFASE--VSNVLNKGHPK--V 96

                          90       100       110
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gi 1720365268  81 QDKVLALIQAWADAFRSSPDLTGVVHIYEELKRRG 115
Cdd:cd17000    97 CEKLKALMVEWTEEFKNDPQLSLISAMIKNLKEQG 131

canonical GAT domain found in uncharacterized Golgi-localized gamma ear-containing Arf-binding protein (GGA)-like proteins mainly found in plants; The family includes a group of uncharacterized plant proteins containing an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. Both domains are also present in Golgi-localized gamma ear-containing Arf-binding proteins (GGAs), which belong to a family of ubiquitously expressed, monomeric, motif-binding cargo/clathrin adaptor proteins that regulate clathrin-mediated trafficking of cargo proteins from the trans-Golgi network (TGN) to endosomes. In contrast to GGA proteins, members in this family do not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

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gi 1720365268 194 ELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNNVFLRYE 270
Cdd:cd14231     1 DLQVARNSLELLSDMLNAVDPRDPEALKDELTVDLVEQCRQSQPRVMQLVESTGDEGLLFQALELNDELQRVLSKHD 77

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

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gi 1720365268 198 VRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELIS-RVSNEEVTEELLHVNDDLNNVFLRY 269
Cdd:cd14239    12 VNNNVKLLTEMLMSYSRGELSESSEELMKELYQRCEKMRPTLFRLASdTEDNDEALAEILQANDNLTQVINLY 84

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.

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gi 1720365268 194 ELDIVRGNTKVMSEMLTEMVPGQEDSSDLELLQELNRTCRAMQHRIVELISRVS-NEEVTEELLHVNDDLNNVFLRYE 270
Cdd:cd14230     1 TLEEAKNNVDLLDEMLLSYSQEDSSDGDNELMKELYDQLENMRPTLFKLASETEeNDNSLGDVLQASDNVNRVINKYK 78

canonical GAT domain found in yeast LAS seventeen-binding protein 5 (Lsb5p) and similar proteins; Lsb5p, also called LAS17-binding protein 5, is a Golgi-localized gamma ear-containing Arf-binding protein (GGA)-like protein located to the plasma membrane in an actin-independent manner. It plays important roles in membrane-trafficking events through association with the actin regulators, the yeast Wiskott-Aldrich syndrome protein (WASP) homologue Las17p and the cortical protein Sla1p, the yeast Arf3p (orthologous with mammalian Arf6), and ubiquitin. Lsb5p contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. In contrast to GGA proteins, Lsb5p harbors a C-terminal NPF (Asn-Pro-Phe) motif, but does not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif. The canonical GAT domain is a monomeric three-helix bundle that binds ubiquitin.

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gi 1720365268 214 PGQEDSSDLELLQELNRTCRAMQHRIVELISRVSNEEVTEELLHVNDDLNNVFLRYER 271
Cdd:cd14232    20 RETERVSDDAEVQERFEKCKQLRRKILRYIQLVEDEEYLGSLLHANEELVAALEAYDE 77