GGA3_HUMAN
ID GGA3_HUMAN Reviewed; 723 AA.
AC Q9NZ52; B7Z7E2; B7Z7M9; J3KRN0; Q15017; Q6IS16; Q9UJY3;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2000, sequence version 1.
DT 03-AUG-2022, entry version 215.
DE RecName: Full=ADP-ribosylation factor-binding protein GGA3 {ECO:0000305};
DE AltName: Full=Golgi-localized, gamma ear-containing, ARF-binding protein 3;
GN Name=GGA3 {ECO:0000312|MIM:606006}; Synonyms=KIAA0154;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT).
RC TISSUE=Heart;
RX PubMed=10747089; DOI=10.1083/jcb.149.1.81;
RA Dell'Angelica E.C., Puertollano R., Mullins C., Aguilar R.C., Vargas J.D.,
RA Hartnell L.M., Bonifacino J.S.;
RT "GGAs: a family of ADP ribosylation factor-binding proteins related to
RT adaptors and associated with the Golgi complex.";
RL J. Cell Biol. 149:81-94(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM SHORT), AND SUBCELLULAR LOCATION.
RX PubMed=10749927; DOI=10.1091/mbc.11.4.1241;
RA Boman A.L., Zhang C.-J., Zhu X., Kahn R.A.;
RT "A family of ADP-ribosylation factor effectors that can alter transport
RT through the trans-Golgi.";
RL Mol. Biol. Cell 11:1241-1255(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT).
RC TISSUE=Bone marrow;
RX PubMed=8590280; DOI=10.1093/dnares/2.4.167;
RA Nagase T., Seki N., Tanaka A., Ishikawa K., Nomura N.;
RT "Prediction of the coding sequences of unidentified human genes. IV. The
RT coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of
RT cDNA clones from human cell line KG-1.";
RL DNA Res. 2:167-174(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4).
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM SHORT).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH SYNRG.
RX PubMed=10814529; DOI=10.1006/bbrc.2000.2700;
RA Takatsu H., Yoshino K., Nakayama K.;
RT "Adaptor gamma ear homology domain conserved in gamma-adaptin and GGA
RT proteins that interact with gamma-synergin.";
RL Biochem. Biophys. Res. Commun. 271:719-725(2000).
RN [9]
RP MUTAGENESIS OF ASN-194; SER-199 AND THR-217, INTERACTION WITH ARF1 AND
RP CLATHRIN, AND FUNCTION.
RX PubMed=11301005; DOI=10.1016/s0092-8674(01)00299-9;
RA Puertollano R., Randazzo P.A., Presley J.F., Hartnell L.M.,
RA Bonifacino J.S.;
RT "The GGAs promote ARF-dependent recruitment of clathrin to the TGN.";
RL Cell 105:93-102(2001).
RN [10]
RP INTERACTION WITH M6PR AND IGF2R.
RX PubMed=11387475; DOI=10.1126/science.1060750;
RA Puertollano R., Aguilar R.C., Gorshkova I., Crouch R.J., Bonifacino J.S.;
RT "Sorting of mannose 6-phosphate receptors mediated by the GGAs.";
RL Science 292:1712-1716(2001).
RN [11]
RP INTERACTION WITH ARF1; ARF5 AND ARF6, AND SUBCELLULAR LOCATION.
RX PubMed=11950392; DOI=10.1042/bj20020428;
RA Takatsu H., Yoshino K., Toda K., Nakayama K.;
RT "GGA proteins associate with Golgi membranes through interaction between
RT their GGAH domains and ADP-ribosylation factors.";
RL Biochem. J. 365:369-378(2002).
RN [12]
RP INTERACTION WITH EPN4.
RX PubMed=12213833; DOI=10.1083/jcb.200205078;
RA Wasiak S., Legendre-Guillemin V., Puertollano R., Blondeau F., Girard M.,
RA de Heuvel E., Boismenu D., Bell A.W., Bonifacino J.S., McPherson P.S.;
RT "Enthoprotin: a novel clathrin-associated protein identified through
RT subcellular proteomics.";
RL J. Cell Biol. 158:855-862(2002).
RN [13]
RP MUTAGENESIS OF 391-ASP--LEU-395, INTERACTION WITH IGF2R, AND
RP AUTOINHIBITION.
RX PubMed=12060753; DOI=10.1073/pnas.082235699;
RA Doray B., Bruns K., Ghosh P., Kornfeld S.A.;
RT "Autoinhibition of the ligand-binding site of GGA1/3 VHS domains by an
RT internal acidic cluster-dileucine motif.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:8072-8077(2002).
RN [14]
RP INTERACTION WITH BACE1.
RX PubMed=14567678; DOI=10.1021/bi035199h;
RA He X., Zhu G., Koelsch G., Rodgers K.K., Zhang X.C., Tang J.;
RT "Biochemical and structural characterization of the interaction of memapsin
RT 2 (beta-secretase) cytosolic domain with the VHS domain of GGA proteins.";
RL Biochemistry 42:12174-12180(2003).
RN [15]
RP INTERACTION WITH RABEP1 AND RABGEF1.
RX PubMed=12505986; DOI=10.1093/emboj/cdg015;
RA Mattera R., Arighi C.N., Lodge R., Zerial M., Bonifacino J.S.;
RT "Divalent interaction of the GGAs with the Rabaptin-5-Rabex-5 complex.";
RL EMBO J. 22:78-88(2003).
RN [16]
RP INTERACTION WITH GGA1 AND GGA2.
RX PubMed=14638859; DOI=10.1083/jcb.200308038;
RA Ghosh P., Griffith J., Geuze H.J., Kornfeld S.;
RT "Mammalian GGAs act together to sort mannose 6-phosphate receptors.";
RL J. Cell Biol. 163:755-766(2003).
RN [17]
RP MUTAGENESIS OF LEU-247; LEU-262; LEU-276; LEU-280; ASP-284 AND TYR-293,
RP INTERACTION WITH UBC, AND UBIQUITINATION.
RX PubMed=14660606; DOI=10.1074/jbc.m311702200;
RA Shiba Y., Katoh Y., Shiba T., Yoshino K., Takatsu H., Kobayashi H.,
RA Shin H.-W., Wakatsuki S., Nakayama K.;
RT "GAT (GGA and Tom1) domain responsible for ubiquitin binding and
RT ubiquitination.";
RL J. Biol. Chem. 279:7105-7111(2004).
RN [18]
RP INTERACTION WITH NECAP1; NECAP2 AND AFTPH.
RX PubMed=14665628; DOI=10.1074/jbc.m311873200;
RA Mattera R., Ritter B., Sidhu S.S., McPherson P.S., Bonifacino J.S.;
RT "Definition of the consensus motif recognized by gamma-adaptin ear
RT domains.";
RL J. Biol. Chem. 279:8018-8028(2004).
RN [19]
RP MUTAGENESIS OF LYS-258 AND SER-283, AND INTERACTION WITH RABEP1.
RX PubMed=15143060; DOI=10.1074/jbc.m402183200;
RA Mattera R., Puertollano R., Smith W.J., Bonifacino J.S.;
RT "The trihelical bundle subdomain of the GGA proteins interacts with
RT multiple partners through overlapping but distinct sites.";
RL J. Biol. Chem. 279:31409-31418(2004).
RN [20]
RP SUBCELLULAR LOCATION, MUTAGENESIS OF LEU-276, AND INTERACTION WITH UBC AND
RP TSG101.
RX PubMed=15039775; DOI=10.1038/ncb1106;
RA Puertollano R., Bonifacino J.S.;
RT "Interactions of GGA3 with the ubiquitin sorting machinery.";
RL Nat. Cell Biol. 6:244-251(2004).
RN [21]
RP FUNCTION.
RX PubMed=15615712; DOI=10.1074/jbc.m411296200;
RA He X., Li F., Chang W.P., Tang J.;
RT "GGA proteins mediate the recycling pathway of memapsin 2 (BACE).";
RL J. Biol. Chem. 280:11696-11703(2005).
RN [22]
RP FUNCTION, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-313; ASP-328;
RP ASP-333 AND ASP-428.
RX PubMed=17553422; DOI=10.1016/j.neuron.2007.05.012;
RA Tesco G., Koh Y.H., Kang E.L., Cameron A.N., Das S., Sena-Esteves M.,
RA Hiltunen M., Yang S.H., Zhong Z., Shen Y., Simpkins J.W., Tanzi R.E.;
RT "Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity.";
RL Neuron 54:721-737(2007).
RN [23]
RP FUNCTION, AND MUTAGENESIS OF ASN-91 AND LEU-276.
RX PubMed=20484053; DOI=10.1074/jbc.m109.092742;
RA Kang E.L., Cameron A.N., Piazza F., Walker K.R., Tesco G.;
RT "Ubiquitin regulates GGA3-mediated degradation of BACE1.";
RL J. Biol. Chem. 285:24108-24119(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-159 AND SER-275, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [26]
RP INTERACTION WITH NTRK1, AND MUTAGENESIS OF LEU-276.
RX PubMed=26446845; DOI=10.1091/mbc.e15-02-0087;
RA Li X., Lavigne P., Lavoie C.;
RT "GGA3 mediates TrkA endocytic recycling to promote sustained Akt
RT phosphorylation and cell survival.";
RL Mol. Biol. Cell 26:4412-4426(2015).
RN [27]
RP FUNCTION, AND INTERACTION WITH ADRA2B.
RX PubMed=26811329; DOI=10.1128/mcb.00009-16;
RA Zhang M., Davis J.E., Li C., Gao J., Huang W., Lambert N.A.,
RA Terry A.V. Jr., Wu G.;
RT "GGA3 Interacts with a G Protein-Coupled Receptor and Modulates Its Cell
RT Surface Export.";
RL Mol. Cell. Biol. 36:1152-1163(2016).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-166.
RX PubMed=12032548; DOI=10.1038/nsb807;
RA Kato Y., Misra S., Puertollano R., Hurley J.H., Bonifacino J.S.;
RT "Phosphoregulation of sorting signal-VHS domain interactions by a direct
RT electrostatic mechanism.";
RL Nat. Struct. Biol. 9:532-536(2002).
RN [29]
RP VARIANT [LARGE SCALE ANALYSIS] LEU-574.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [30]
RP VARIANTS ARG-132 AND GLY-321.
RX PubMed=26477546; DOI=10.1016/j.ajhg.2015.09.009;
RG Care4Rare Canada Consortium;
RA Srour M., Hamdan F.F., McKnight D., Davis E., Mandel H.,
RA Schwartzentruber J., Martin B., Patry L., Nassif C., Dionne-Laporte A.,
RA Ospina L.H., Lemyre E., Massicotte C., Laframboise R., Maranda B.,
RA Labuda D., Decarie J.C., Rypens F., Goldsher D., Fallet-Bianco C.,
RA Soucy J.F., Laberge A.M., Maftei C., Boycott K., Brais B., Boucher R.M.,
RA Rouleau G.A., Katsanis N., Majewski J., Elpeleg O., Kukolich M.K.,
RA Shalev S., Michaud J.L.;
RT "Joubert Syndrome in French Canadians and Identification of Mutations in
RT CEP104.";
RL Am. J. Hum. Genet. 97:744-753(2015).
CC -!- FUNCTION: Plays a role in protein sorting and trafficking between the
CC trans-Golgi network (TGN) and endosomes. Mediates the ARF-dependent
CC recruitment of clathrin to the TGN and binds ubiquitinated proteins and
CC membrane cargo molecules with a cytosolic acidic cluster-dileucine
CC (DXXLL) motif (PubMed:11301005). Mediates export of the GPCR receptor
CC ADRA2B to the cell surface (PubMed:26811329). nvolved in BACE1
CC transport and sorting as well as regulation of BACE1 protein levels
CC (PubMed:17553422, PubMed:15615712, PubMed:20484053). Regulates
CC retrograde transport of BACE1 from endosomes to the trans-Golgi network
CC via interaction through the VHS motif and dependent of BACE1
CC phosphorylation (PubMed:15615712). Modulates BACE1 protein levels
CC independently of the interaction between VHS domain and DXXLL motif
CC through recognition of ubiquitination (PubMed:20484053). Key player in
CC a novel DXXLL-mediated endosomal sorting machinery to the recycling
CC pathway that targets NTRK1 to the plasma membrane (By similarity).
CC {ECO:0000250|UniProtKB:A0A0G2JV04, ECO:0000269|PubMed:11301005,
CC ECO:0000269|PubMed:15615712, ECO:0000269|PubMed:17553422,
CC ECO:0000269|PubMed:20484053, ECO:0000269|PubMed:26811329}.
CC -!- SUBUNIT: Monomer (Probable). Interacts with GGA1 and GGA2
CC (PubMed:14638859). Binds to clathrin and activated ARFs, such as ARF1,
CC ARF5 and ARF6 (PubMed:11301005, PubMed:11950392). Binds RABEP1 and
CC RABGEF1 (PubMed:12505986, PubMed:15143060). Interacts with the membrane
CC proteins M6PR/CD-MPR and IGF2R/CI-MPR and the accessory proteins SYNRG,
CC EPN4, NECAP1, NECAP2 and AFTPH/aftiphilin (PubMed:10814529,
CC PubMed:11387475, PubMed:12060753, PubMed:12213833, PubMed:14665628).
CC Interacts with TSG101 and UBC (PubMed:14660606, PubMed:15039775).
CC Interacts with ADRA2B (PubMed:26811329). Interacts with NTRK1; the
CC interaction is independent of NTRK1 activation and ubiquitination
CC (PubMed:26446845). Interacts (via VHS domain) with BACE1 (via DXXLL
CC motif) (PubMed:14567678). {ECO:0000269|PubMed:10814529,
CC ECO:0000269|PubMed:11301005, ECO:0000269|PubMed:11387475,
CC ECO:0000269|PubMed:11950392, ECO:0000269|PubMed:12060753,
CC ECO:0000269|PubMed:12213833, ECO:0000269|PubMed:12505986,
CC ECO:0000269|PubMed:14567678, ECO:0000269|PubMed:14638859,
CC ECO:0000269|PubMed:14660606, ECO:0000269|PubMed:14665628,
CC ECO:0000269|PubMed:15039775, ECO:0000269|PubMed:15143060,
CC ECO:0000269|PubMed:26446845, ECO:0000269|PubMed:26811329, ECO:0000305}.
CC -!- INTERACTION:
CC Q9NZ52; P62330: ARF6; NbExp=3; IntAct=EBI-447404, EBI-638181;
CC Q9NZ52; P56817: BACE1; NbExp=2; IntAct=EBI-447404, EBI-2433139;
CC Q9NZ52; Q9UJY5: GGA1; NbExp=4; IntAct=EBI-447404, EBI-447141;
CC Q9NZ52; Q9UJY4: GGA2; NbExp=3; IntAct=EBI-447404, EBI-447646;
CC Q9NZ52; P11717: IGF2R; NbExp=3; IntAct=EBI-447404, EBI-1048580;
CC Q9NZ52; Q6VY07: PACS1; NbExp=5; IntAct=EBI-447404, EBI-2555014;
CC Q9NZ52; Q15276: RABEP1; NbExp=4; IntAct=EBI-447404, EBI-447043;
CC Q9NZ52; Q99816: TSG101; NbExp=2; IntAct=EBI-447404, EBI-346882;
CC Q9NZ52; P0CG47: UBB; NbExp=2; IntAct=EBI-447404, EBI-413034;
CC Q9NZ52-2; Q15038: DAZAP2; NbExp=3; IntAct=EBI-12075758, EBI-724310;
CC Q9NZ52-2; Q99732: LITAF; NbExp=3; IntAct=EBI-12075758, EBI-725647;
CC Q9NZ52-2; Q7Z4N8: P4HA3; NbExp=3; IntAct=EBI-12075758, EBI-10181968;
CC Q9NZ52-2; Q96CS7: PLEKHB2; NbExp=3; IntAct=EBI-12075758, EBI-373552;
CC Q9NZ52-2; O75865-2: TRAPPC6A; NbExp=3; IntAct=EBI-12075758, EBI-8451480;
CC Q9NZ52-2; P36406: TRIM23; NbExp=3; IntAct=EBI-12075758, EBI-740098;
CC Q9NZ52-2; Q96BW1: UPRT; NbExp=3; IntAct=EBI-12075758, EBI-742943;
CC Q9NZ52-2; Q6ZNH5: ZNF497; NbExp=3; IntAct=EBI-12075758, EBI-10486136;
CC -!- SUBCELLULAR LOCATION: Golgi apparatus, trans-Golgi network membrane
CC {ECO:0000269|PubMed:10749927, ECO:0000269|PubMed:15039775}; Peripheral
CC membrane protein {ECO:0000269|PubMed:10749927,
CC ECO:0000269|PubMed:15039775}. Endosome membrane
CC {ECO:0000269|PubMed:15039775}; Peripheral membrane protein
CC {ECO:0000269|PubMed:15039775}. Early endosome membrane
CC {ECO:0000269|PubMed:11950392}; Peripheral membrane protein
CC {ECO:0000305}. Recycling endosome membrane
CC {ECO:0000250|UniProtKB:A0A0G2JV04}; Peripheral membrane protein
CC {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=Long;
CC IsoId=Q9NZ52-1; Sequence=Displayed;
CC Name=Short;
CC IsoId=Q9NZ52-2; Sequence=VSP_001745;
CC Name=3;
CC IsoId=Q9NZ52-3; Sequence=VSP_045133, VSP_045134;
CC Name=4;
CC IsoId=Q9NZ52-4; Sequence=VSP_046868;
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DOMAIN: The VHS domain functions as a recognition module for sorting
CC signals composed of an acidic cluster followed by two leucines (DXXLL
CC motif). {ECO:0000305|PubMed:14567678, ECO:0000305|PubMed:20484053}.
CC -!- DOMAIN: The GAT domain is responsible for interaction with ARF-GTP, UBC
CC and RABEP1. Required for recruitment to the TGN it prevents ARF-GTP
CC hydrolysis.
CC -!- DOMAIN: The unstructured hinge region contains clathrin-binding and an
CC autoinhibitory (DXXLL) motifs.
CC -!- DOMAIN: The GAE domain binds accessory proteins regulating GGAs
CC function.
CC -!- PTM: Phosphorylated by CK2 and dephosphorylated by PP2A (By
CC similarity). Phosphorylation of GGA3 allows the internal DXXLL motif to
CC bind the VHS domain and to inhibit the recognition of cargo signals.
CC {ECO:0000250}.
CC -!- PTM: Ubiquitinated. {ECO:0000269|PubMed:14660606}.
CC -!- PTM: Proteolytically cleaved during apoptosis by CASP3.
CC {ECO:0000269|PubMed:17553422}.
CC -!- SIMILARITY: Belongs to the GGA protein family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA09926.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF219138; AAF42848.1; -; mRNA.
DR EMBL; AF190864; AAF05709.1; -; mRNA.
DR EMBL; AF219139; AAF42849.1; -; mRNA.
DR EMBL; D63876; BAA09926.1; ALT_INIT; mRNA.
DR EMBL; AK301895; BAH13578.1; -; mRNA.
DR EMBL; AK302278; BAH13665.1; -; mRNA.
DR EMBL; AC022211; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471099; EAW89258.1; -; Genomic_DNA.
DR EMBL; BC070044; AAH70044.1; -; mRNA.
DR CCDS; CCDS11716.1; -. [Q9NZ52-2]
DR CCDS; CCDS11717.1; -. [Q9NZ52-1]
DR CCDS; CCDS54164.1; -. [Q9NZ52-4]
DR CCDS; CCDS58597.1; -. [Q9NZ52-3]
DR RefSeq; NP_001166174.1; NM_001172703.2. [Q9NZ52-4]
DR RefSeq; NP_001166175.1; NM_001172704.2. [Q9NZ52-3]
DR RefSeq; NP_001278570.1; NM_001291641.1. [Q9NZ52-4]
DR RefSeq; NP_001278571.1; NM_001291642.1.
DR RefSeq; NP_054720.1; NM_014001.4. [Q9NZ52-2]
DR RefSeq; NP_619525.1; NM_138619.3. [Q9NZ52-1]
DR PDB; 1JPL; X-ray; 2.40 A; A/B/C/D=1-166.
DR PDB; 1JUQ; X-ray; 2.20 A; A/B/C/D=1-166.
DR PDB; 1LF8; X-ray; 2.30 A; A/B/C/D=1-166.
DR PDB; 1P4U; X-ray; 2.20 A; A=571-723.
DR PDB; 1WR6; X-ray; 2.60 A; A/B/C/D=209-319.
DR PDB; 1YD8; X-ray; 2.80 A; G/H=208-301.
DR PDBsum; 1JPL; -.
DR PDBsum; 1JUQ; -.
DR PDBsum; 1LF8; -.
DR PDBsum; 1P4U; -.
DR PDBsum; 1WR6; -.
DR PDBsum; 1YD8; -.
DR AlphaFoldDB; Q9NZ52; -.
DR SMR; Q9NZ52; -.
DR BioGRID; 116775; 96.
DR DIP; DIP-31600N; -.
DR ELM; Q9NZ52; -.
DR IntAct; Q9NZ52; 31.
DR MINT; Q9NZ52; -.
DR STRING; 9606.ENSP00000438085; -.
DR TCDB; 9.B.278.1.3; the organellar-targeting adaptor protein complex (o-apc) family.
DR GlyGen; Q9NZ52; 4 sites, 1 O-linked glycan (4 sites).
DR iPTMnet; Q9NZ52; -.
DR PhosphoSitePlus; Q9NZ52; -.
DR BioMuta; GGA3; -.
DR DMDM; 14548064; -.
DR EPD; Q9NZ52; -.
DR jPOST; Q9NZ52; -.
DR MassIVE; Q9NZ52; -.
DR MaxQB; Q9NZ52; -.
DR PaxDb; Q9NZ52; -.
DR PeptideAtlas; Q9NZ52; -.
DR PRIDE; Q9NZ52; -.
DR ProteomicsDB; 83324; -. [Q9NZ52-1]
DR ProteomicsDB; 83325; -. [Q9NZ52-2]
DR Antibodypedia; 19520; 198 antibodies from 32 providers.
DR DNASU; 23163; -.
DR Ensembl; ENST00000537686.6; ENSP00000438085.3; ENSG00000125447.18. [Q9NZ52-1]
DR Ensembl; ENST00000538886.5; ENSP00000446421.2; ENSG00000125447.18. [Q9NZ52-2]
DR Ensembl; ENST00000578348.5; ENSP00000463288.1; ENSG00000125447.18. [Q9NZ52-3]
DR Ensembl; ENST00000582717.5; ENSP00000462081.1; ENSG00000125447.18. [Q9NZ52-4]
DR Ensembl; ENST00000649398.1; ENSP00000496890.1; ENSG00000125447.18. [Q9NZ52-1]
DR GeneID; 23163; -.
DR KEGG; hsa:23163; -.
DR MANE-Select; ENST00000537686.6; ENSP00000438085.3; NM_138619.4; NP_619525.1.
DR UCSC; uc010wrw.3; human. [Q9NZ52-1]
DR CTD; 23163; -.
DR DisGeNET; 23163; -.
DR GeneCards; GGA3; -.
DR HGNC; HGNC:17079; GGA3.
DR HPA; ENSG00000125447; Low tissue specificity.
DR MIM; 606006; gene.
DR neXtProt; NX_Q9NZ52; -.
DR OpenTargets; ENSG00000125447; -.
DR PharmGKB; PA28659; -.
DR VEuPathDB; HostDB:ENSG00000125447; -.
DR eggNOG; KOG1087; Eukaryota.
DR GeneTree; ENSGT00940000157333; -.
DR HOGENOM; CLU_015010_0_0_1; -.
DR InParanoid; Q9NZ52; -.
DR OMA; MQLLNQM; -.
DR OrthoDB; 594067at2759; -.
DR PhylomeDB; Q9NZ52; -.
DR TreeFam; TF318574; -.
DR PathwayCommons; Q9NZ52; -.
DR Reactome; R-HSA-8854214; TBC/RABGAPs.
DR Reactome; R-HSA-8875656; MET receptor recycling.
DR Reactome; R-HSA-977225; Amyloid fiber formation.
DR SignaLink; Q9NZ52; -.
DR BioGRID-ORCS; 23163; 37 hits in 1075 CRISPR screens.
DR ChiTaRS; GGA3; human.
DR EvolutionaryTrace; Q9NZ52; -.
DR GeneWiki; GGA3; -.
DR GenomeRNAi; 23163; -.
DR Pharos; Q9NZ52; Tbio.
DR PRO; PR:Q9NZ52; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q9NZ52; protein.
DR Bgee; ENSG00000125447; Expressed in sural nerve and 180 other tissues.
DR ExpressionAtlas; Q9NZ52; baseline and differential.
DR Genevisible; Q9NZ52; HS.
DR GO; GO:0031901; C:early endosome membrane; TAS:Reactome.
DR GO; GO:0010008; C:endosome membrane; TAS:Reactome.
DR GO; GO:0005794; C:Golgi apparatus; IDA:HPA.
DR GO; GO:0005764; C:lysosome; IDA:ARUK-UCL.
DR GO; GO:0032991; C:protein-containing complex; IDA:ARUK-UCL.
DR GO; GO:0055038; C:recycling endosome membrane; TAS:Reactome.
DR GO; GO:0005802; C:trans-Golgi network; IDA:UniProtKB.
DR GO; GO:0035091; F:phosphatidylinositol binding; IEA:InterPro.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:ARUK-UCL.
DR GO; GO:0031267; F:small GTPase binding; IDA:UniProtKB.
DR GO; GO:0043130; F:ubiquitin binding; IDA:UniProtKB.
DR GO; GO:0032456; P:endocytic recycling; IEA:Ensembl.
DR GO; GO:0043001; P:Golgi to plasma membrane protein transport; IMP:UniProtKB.
DR GO; GO:0006893; P:Golgi to plasma membrane transport; IBA:GO_Central.
DR GO; GO:0006886; P:intracellular protein transport; NAS:UniProtKB.
DR GO; GO:1902430; P:negative regulation of amyloid-beta formation; IDA:UniProtKB.
DR GO; GO:0045732; P:positive regulation of protein catabolic process; IEA:Ensembl.
DR GO; GO:0030163; P:protein catabolic process; IEA:Ensembl.
DR GO; GO:0031648; P:protein destabilization; IDA:UniProtKB.
DR GO; GO:0034394; P:protein localization to cell surface; IMP:UniProtKB.
DR GO; GO:0006622; P:protein targeting to lysosome; IPI:ARUK-UCL.
DR GO; GO:0031647; P:regulation of protein stability; IDA:UniProtKB.
DR CDD; cd14240; GAT_GGA3; 1.
DR Gene3D; 1.20.58.160; -; 1.
DR Gene3D; 1.25.40.90; -; 1.
DR InterPro; IPR008152; Clathrin_a/b/g-adaptin_app_Ig.
DR InterPro; IPR013041; Clathrin_app_Ig-like_sf.
DR InterPro; IPR008942; ENTH_VHS.
DR InterPro; IPR008153; GAE_dom.
DR InterPro; IPR004152; GAT_dom.
DR InterPro; IPR044111; GAT_GGA3.
DR InterPro; IPR038425; GAT_sf.
DR InterPro; IPR027422; GGA3.
DR InterPro; IPR041198; GGA_N-GAT.
DR InterPro; IPR002014; VHS_dom.
DR PANTHER; PTHR45905:SF3; PTHR45905:SF3; 1.
DR Pfam; PF02883; Alpha_adaptinC2; 1.
DR Pfam; PF03127; GAT; 1.
DR Pfam; PF18308; GGA_N-GAT; 1.
DR Pfam; PF00790; VHS; 1.
DR SMART; SM00809; Alpha_adaptinC2; 1.
DR SMART; SM00288; VHS; 1.
DR SUPFAM; SSF48464; SSF48464; 1.
DR SUPFAM; SSF49348; SSF49348; 1.
DR PROSITE; PS50180; GAE; 1.
DR PROSITE; PS50909; GAT; 1.
DR PROSITE; PS50179; VHS; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Endosome; Golgi apparatus; Membrane;
KW Phosphoprotein; Protein transport; Reference proteome; Transport;
KW Ubl conjugation.
FT CHAIN 1..723
FT /note="ADP-ribosylation factor-binding protein GGA3"
FT /id="PRO_0000212684"
FT DOMAIN 16..146
FT /note="VHS"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00218"
FT DOMAIN 171..298
FT /note="GAT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00373"
FT DOMAIN 594..715
FT /note="GAE"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00093"
FT REGION 1..313
FT /note="Binds to ARF1 (in long isoform)"
FT REGION 299..593
FT /note="Unstructured hinge"
FT REGION 339..384
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 428..464
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 391..395
FT /note="DXXLL"
FT /evidence="ECO:0000269|PubMed:12060753"
FT COMPBIAS 347..365
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 366..384
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 159
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT MOD_RES 275
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:24275569"
FT VAR_SEQ 1..122
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045133"
FT VAR_SEQ 1..72
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046868"
FT VAR_SEQ 68..100
FT /note="Missing (in isoform Short)"
FT /evidence="ECO:0000303|PubMed:10747089,
FT ECO:0000303|PubMed:10749927, ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:8590280"
FT /id="VSP_001745"
FT VAR_SEQ 688..723
FT /note="EKVRLRYKLTFALGEQLSTEVGEVDQFPPVEQWGNL -> KQVLSFLGKACL
FT QPWGQAILLTTSCLA (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045134"
FT VARIANT 132
FT /note="K -> R (in dbSNP:rs117805695)"
FT /evidence="ECO:0000269|PubMed:26477546"
FT /id="VAR_075715"
FT VARIANT 321
FT /note="S -> G (in dbSNP:rs146877619)"
FT /evidence="ECO:0000269|PubMed:26477546"
FT /id="VAR_075716"
FT VARIANT 574
FT /note="P -> L (in a breast cancer sample; somatic mutation;
FT dbSNP:rs776324450)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036524"
FT MUTAGEN 91
FT /note="N->A: No effect on regulation of BACE1 degradation."
FT /evidence="ECO:0000269|PubMed:20484053"
FT MUTAGEN 194
FT /note="N->A: Loss of interaction with ARF1 and Golgi
FT localization."
FT /evidence="ECO:0000269|PubMed:11301005"
FT MUTAGEN 199
FT /note="S->P: Loss of interaction with ARF1 and Golgi
FT localization."
FT /evidence="ECO:0000269|PubMed:11301005"
FT MUTAGEN 217
FT /note="T->P: Loss of interaction with ARF1 and Golgi
FT localization."
FT /evidence="ECO:0000269|PubMed:11301005"
FT MUTAGEN 247
FT /note="L->P: Loss of UBC-binding and ubiquitination."
FT /evidence="ECO:0000269|PubMed:14660606"
FT MUTAGEN 258
FT /note="K->M: No effect. Confers an affinity to RABEP1
FT identical to GGA1; when associated with N-283."
FT /evidence="ECO:0000269|PubMed:15143060"
FT MUTAGEN 262
FT /note="L->S: Loss of UBC-binding and ubiquitination."
FT /evidence="ECO:0000269|PubMed:14660606"
FT MUTAGEN 276
FT /note="L->A: Loss of UBC-binding and ubiquitination.
FT Abolishes binding to ubiquitin. Abolishes regulation of
FT BACE1 degradation. No effect on interaction with NTRK1."
FT /evidence="ECO:0000269|PubMed:14660606,
FT ECO:0000269|PubMed:15039775, ECO:0000269|PubMed:20484053,
FT ECO:0000269|PubMed:26446845"
FT MUTAGEN 276
FT /note="L->S: Loss of UBC-binding and ubiquitination."
FT /evidence="ECO:0000269|PubMed:14660606,
FT ECO:0000269|PubMed:15039775"
FT MUTAGEN 280
FT /note="L->R: Loss of UBC-binding and ubiquitination."
FT /evidence="ECO:0000269|PubMed:14660606"
FT MUTAGEN 283
FT /note="S->N: Can bind RABEP1. Confers an affinity to RABEP1
FT identical to GGA1; when associated with M-258."
FT /evidence="ECO:0000269|PubMed:15143060"
FT MUTAGEN 284
FT /note="D->G: Loss of UBC-binding and ubiquitination."
FT /evidence="ECO:0000269|PubMed:14660606"
FT MUTAGEN 293
FT /note="Y->H: Loss of UBC-binding and ubiquitination."
FT /evidence="ECO:0000269|PubMed:14660606"
FT MUTAGEN 313
FT /note="D->A: Acts as dominant negative. Prevents
FT proteolytic cleavage by CASP3; when associated with A-328,
FT A-333 and A-428."
FT /evidence="ECO:0000269|PubMed:17553422"
FT MUTAGEN 328
FT /note="D->A: Prevents proteolytic cleavage by CASP3; when
FT associated with A-313, A-333 and A-428."
FT /evidence="ECO:0000269|PubMed:17553422"
FT MUTAGEN 333
FT /note="D->A: Prevents proteolytic cleavage by CASP3; when
FT associated with A-313, A-328 and A-428."
FT /evidence="ECO:0000269|PubMed:17553422"
FT MUTAGEN 391..395
FT /note="DEELL->AAAAA: Increased binding to IGF2R."
FT /evidence="ECO:0000269|PubMed:12060753"
FT MUTAGEN 428
FT /note="D->A: Prevents proteolytic cleavage by CASP3; when
FT associated with A-313, A-328 and A-333."
FT /evidence="ECO:0000269|PubMed:17553422"
FT CONFLICT 448
FT /note="Q -> K (in Ref. 7; AAH70044)"
FT /evidence="ECO:0000305"
FT CONFLICT 562
FT /note="F -> S (in Ref. 4; BAH13665)"
FT /evidence="ECO:0000305"
FT HELIX 9..16
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 26..38
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 42..54
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 59..75
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 77..84
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 87..97
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 99..103
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 108..124
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 129..140
FT /evidence="ECO:0007829|PDB:1JUQ"
FT HELIX 218..231
FT /evidence="ECO:0007829|PDB:1WR6"
FT TURN 232..234
FT /evidence="ECO:0007829|PDB:1WR6"
FT TURN 237..239
FT /evidence="ECO:0007829|PDB:1WR6"
FT HELIX 242..267
FT /evidence="ECO:0007829|PDB:1WR6"
FT HELIX 276..290
FT /evidence="ECO:0007829|PDB:1WR6"
FT HELIX 292..295
FT /evidence="ECO:0007829|PDB:1WR6"
FT TURN 296..298
FT /evidence="ECO:0007829|PDB:1WR6"
FT HELIX 588..590
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 599..604
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 607..616
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 624..633
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 635..637
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 639..647
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 652..656
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 675..683
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 692..700
FT /evidence="ECO:0007829|PDB:1P4U"
FT STRAND 703..711
FT /evidence="ECO:0007829|PDB:1P4U"
FT HELIX 717..719
FT /evidence="ECO:0007829|PDB:1P4U"
SQ SEQUENCE 723 AA; 78315 MW; 4F80D6032239168C CRC64;
MAEAEGESLE SWLNKATNPS NRQEDWEYII GFCDQINKEL EGPQIAVRLL AHKIQSPQEW
EALQALTVLE ACMKNCGRRF HNEVGKFRFL NELIKVVSPK YLGDRVSEKV KTKVIELLYS
WTMALPEEAK IKDAYHMLKR QGIVQSDPPI PVDRTLIPSP PPRPKNPVFD DEEKSKLLAK
LLKSKNPDDL QEANKLIKSM VKEDEARIQK VTKRLHTLEE VNNNVRLLSE MLLHYSQEDS
SDGDRELMKE LFDQCENKRR TLFKLASETE DNDNSLGDIL QASDNLSRVI NSYKTIIEGQ
VINGEVATLT LPDSEGNSQC SNQGTLIDLA ELDTTNSLSS VLAPAPTPPS SGIPILPPPP
QASGPPRSRS SSQAEATLGP SSTSNALSWL DEELLCLGLA DPAPNVPPKE SAGNSQWHLL
QREQSDLDFF SPRPGTAACG ASDAPLLQPS APSSSSSQAP LPPPFPAPVV PASVPAPSAG
SSLFSTGVAP ALAPKVEPAV PGHHGLALGN SALHHLDALD QLLEEAKVTS GLVKPTTSPL
IPTTTPARPL LPFSTGPGSP LFQPLSFQSQ GSPPKGPELS LASIHVPLES IKPSSALPVT
AYDKNGFRIL FHFAKECPPG RPDVLVVVVS MLNTAPLPVK SIVLQAAVPK SMKVKLQPPS
GTELSPFSPI QPPAAITQVM LLANPLKEKV RLRYKLTFAL GEQLSTEVGE VDQFPPVEQW
GNL
