RRAGA_HUMAN
ID RRAGA_HUMAN Reviewed; 313 AA.
AC Q7L523; B2R7L1; O00290; Q15347;
DT 13-JUN-2006, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Ras-related GTP-binding protein A {ECO:0000305};
DE Short=Rag A {ECO:0000303|PubMed:11073942};
DE Short=RagA {ECO:0000303|PubMed:7499430};
DE EC=3.6.5.- {ECO:0000269|PubMed:23723238, ECO:0000305|PubMed:24095279};
DE AltName: Full=Adenovirus E3 14.7 kDa-interacting protein 1 {ECO:0000303|PubMed:8995684};
DE AltName: Full=FIP-1 {ECO:0000303|PubMed:8995684};
GN Name=RRAGA {ECO:0000312|HGNC:HGNC:16963};
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] {ECO:0000312|EMBL:CAA62131.1}
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Fetal brain {ECO:0000312|EMBL:CAA62131.1};
RX PubMed=7499430; DOI=10.1074/jbc.270.48.28982;
RA Schuermann A., Brauers A., Massmann S., Becker W., Joost H.-G.;
RT "Cloning of a novel family of mammalian GTP-binding proteins (RagA, RagBs,
RT RagBl) with remote similarity to the Ras-related GTPases.";
RL J. Biol. Chem. 270:28982-28988(1995).
RN [2] {ECO:0000305, ECO:0000312|EMBL:AAB63255.1}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH ADENOVIRUS E3 14.7
RP KDA PROTEIN (MICROBIAL INFECTION), SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=8995684; DOI=10.1128/jvi.71.2.1576-1582.1997;
RA Li Y., Kang J., Horwitz M.S.;
RT "Interaction of an adenovirus 14.7-kilodalton protein inhibitor of tumor
RT necrosis factor alpha cytolysis with a new member of the GTPase superfamily
RT of signal transducers.";
RL J. Virol. 71:1576-1582(1997).
RN [3] {ECO:0000305}
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=9394008; DOI=10.1242/jcs.111.1.11;
RA Hirose E., Nakashima N., Sekiguchi T., Nishimoto T.;
RT "RagA is a functional homologue of S. cerevisiae Gtr1p involved in the
RT Ran/Gsp1-GTPase pathway.";
RL J. Cell Sci. 111:11-21(1998).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain cortex;
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] {ECO:0000312|EMBL:AL356000}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7] {ECO:0000312|EMBL:AAH06433.1}
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain {ECO:0000312|EMBL:AAH09990.1}, and
RC Ovary {ECO:0000312|EMBL:AAH06433.1};
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] {ECO:0000305}
RP INTERACTION WITH RRAGC AND RRAGD.
RX PubMed=11073942; DOI=10.1074/jbc.m004389200;
RA Sekiguchi T., Hirose E., Nakashima N., Ii M., Nishimoto T.;
RT "Novel G proteins, Rag C and Rag D, interact with GTP-binding proteins, Rag
RT A and Rag B.";
RL J. Biol. Chem. 276:7246-7257(2001).
RN [9] {ECO:0000305}
RP INTERACTION WITH NOL8, SUBUNIT, AND GTP-BINDING.
RX PubMed=14660641; DOI=10.1074/jbc.m305935200;
RA Sekiguchi T., Todaka Y., Wang Y., Hirose E., Nakashima N., Nishimoto T.;
RT "A novel human nucleolar protein, Nop132, binds to the G proteins, RRAG
RT A/C/D.";
RL J. Biol. Chem. 279:8343-8350(2004).
RN [10]
RP INTERACTION WITH RPTOR.
RX PubMed=18497260; DOI=10.1126/science.1157535;
RA Sancak Y., Peterson T.R., Shaul Y.D., Lindquist R.A., Thoreen C.C.,
RA Bar-Peled L., Sabatini D.M.;
RT "The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1.";
RL Science 320:1496-1501(2008).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RRAGC.
RX PubMed=20381137; DOI=10.1016/j.cell.2010.02.024;
RA Sancak Y., Bar-Peled L., Zoncu R., Markhard A.L., Nada S., Sabatini D.M.;
RT "Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is
RT necessary for its activation by amino acids.";
RL Cell 141:290-303(2010).
RN [12]
RP INTERACTION WITH SH3BP4.
RX PubMed=22575674; DOI=10.1016/j.molcel.2012.04.007;
RA Kim Y.M., Stone M., Hwang T.H., Kim Y.G., Dunlevy J.R., Griffin T.J.,
RA Kim D.H.;
RT "SH3BP4 is a negative regulator of amino acid-Rag GTPase-mTORC1
RT signaling.";
RL Mol. Cell 46:833-846(2012).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-309, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [14]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF THR-21.
RX PubMed=24095279; DOI=10.1016/j.molcel.2013.09.016;
RA Tsun Z.Y., Bar-Peled L., Chantranupong L., Zoncu R., Wang T., Kim C.,
RA Spooner E., Sabatini D.M.;
RT "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that
RT signal amino acid levels to mTORC1.";
RL Mol. Cell 52:495-505(2013).
RN [15]
RP CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND INTERACTION WITH THE GATOR1
RP COMPLEX.
RX PubMed=23723238; DOI=10.1126/science.1232044;
RA Bar-Peled L., Chantranupong L., Cherniack A.D., Chen W.W., Ottina K.A.,
RA Grabiner B.C., Spear E.D., Carter S.L., Meyerson M., Sabatini D.M.;
RT "A Tumor suppressor complex with GAP activity for the Rag GTPases that
RT signal amino acid sufficiency to mTORC1.";
RL Science 340:1100-1106(2013).
RN [16]
RP INTERACTION WITH SESN1; SESN2 AND SESN3.
RX PubMed=25259925; DOI=10.1016/j.cell.2014.08.038;
RA Peng M., Yin N., Li M.O.;
RT "Sestrins function as guanine nucleotide dissociation inhibitors for Rag
RT GTPases to control mTORC1 signaling.";
RL Cell 159:122-133(2014).
RN [17]
RP INTERACTION WITH SLC38A9.
RX PubMed=25561175; DOI=10.1038/nature14107;
RA Rebsamen M., Pochini L., Stasyk T., de Araujo M.E., Galluccio M.,
RA Kandasamy R.K., Snijder B., Fauster A., Rudashevskaya E.L., Bruckner M.,
RA Scorzoni S., Filipek P.A., Huber K.V., Bigenzahn J.W., Heinz L.X.,
RA Kraft C., Bennett K.L., Indiveri C., Huber L.A., Superti-Furga G.;
RT "SLC38A9 is a component of the lysosomal amino acid sensing machinery that
RT controls mTORC1.";
RL Nature 519:477-481(2015).
RN [18]
RP INTERACTION WITH SLC38A9.
RX PubMed=25567906; DOI=10.1126/science.1257132;
RA Wang S., Tsun Z.Y., Wolfson R.L., Shen K., Wyant G.A., Plovanich M.E.,
RA Yuan E.D., Jones T.D., Chantranupong L., Comb W., Wang T., Bar-Peled L.,
RA Zoncu R., Straub C., Kim C., Park J., Sabatini B.L., Sabatini D.M.;
RT "Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine
RT sufficiency to mTORC1.";
RL Science 347:188-194(2015).
RN [19]
RP FUNCTION, ACTIVITY REGULATION, UBIQUITINATION AT LYS-142; LYS-220; LYS-230
RP AND LYS-244 BY RNF152, INTERACTION WITH RNF152; TSC2 AND THE GATOR1
RP COMPLEX, AND MUTAGENESIS OF LYS-142; LYS-220; LYS-230 AND LYS-244.
RX PubMed=25936802; DOI=10.1016/j.molcel.2015.03.033;
RA Deng L., Jiang C., Chen L., Jin J., Wei J., Zhao L., Chen M., Pan W.,
RA Xu Y., Chu H., Wang X., Ge X., Li D., Liao L., Liu M., Li L., Wang P.;
RT "The ubiquitination of RagA GTPase by RNF152 negatively regulates mTORC1
RT activation.";
RL Mol. Cell 58:804-818(2015).
RN [20]
RP INTERACTION WITH GPR137B, AND SUBCELLULAR LOCATION.
RX PubMed=31036939; DOI=10.1038/s41556-019-0321-6;
RA Gan L., Seki A., Shen K., Iyer H., Han K., Hayer A., Wollman R., Ge X.,
RA Lin J.R., Dey G., Talbot W.S., Meyer T.;
RT "The lysosomal GPCR-like protein GPR137B regulates Rag and mTORC1
RT localization and activity.";
RL Nat. Cell Biol. 21:614-626(2019).
RN [21] {ECO:0007744|PDB:6ULG}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.31 ANGSTROMS) IN COMPLEX WITH GDP;
RP FLCN; FNIP2; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4 AND LAMTOR5,
RP IDENTIFICATION IN THE LFC COMPLEX, AND MUTAGENESIS OF THR-21.
RX PubMed=31704029; DOI=10.1016/j.cell.2019.10.036;
RA Shen K., Rogala K.B., Chou H.T., Huang R.K., Yu Z., Sabatini D.M.;
RT "Cryo-EM structure of the human FLCN-FNIP2-Rag-Ragulator complex.";
RL Cell 179:1319-1329(2019).
RN [22] {ECO:0007744|PDB:6NZD}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) IN COMPLEX WITH GDP;
RP FLCN; FNIP2; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4 AND LAMTOR5, AND
RP IDENTIFICATION IN THE LFC COMPLEX.
RX PubMed=31672913; DOI=10.1126/science.aax0364;
RA Lawrence R.E., Fromm S.A., Fu Y., Yokom A.L., Kim D.J., Thelen A.M.,
RA Young L.N., Lim C.Y., Samelson A.J., Hurley J.H., Zoncu R.;
RT "Structural mechanism of a Rag GTPase activation checkpoint by the
RT lysosomal folliculin complex.";
RL Science 366:971-977(2019).
CC -!- FUNCTION: Guanine nucleotide-binding protein that plays a crucial role
CC in the cellular response to amino acid availability through regulation
CC of the mTORC1 signaling cascade (PubMed:20381137, PubMed:24095279,
CC PubMed:25936802). Forms heterodimeric Rag complexes with RRAGC or RRAGD
CC and cycles between an inactive GDP-bound and an active GTP-bound form
CC (PubMed:20381137, PubMed:24095279, PubMed:25936802). In its active form
CC participates in the relocalization of mTORC1 to the lysosomes and its
CC subsequent activation by the GTPase RHEB (PubMed:20381137,
CC PubMed:25936802). Involved in the RCC1/Ran-GTPase pathway
CC (PubMed:9394008). May play a direct role in a TNF-alpha signaling
CC pathway leading to induction of cell death (PubMed:8995684).
CC {ECO:0000269|PubMed:20381137, ECO:0000269|PubMed:24095279,
CC ECO:0000269|PubMed:25936802, ECO:0000269|PubMed:8995684,
CC ECO:0000269|PubMed:9394008}.
CC -!- FUNCTION: (Microbial infection) May alternatively act as a cellular
CC target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions,
CC thereby affecting cell death. {ECO:0000269|PubMed:8995684}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=GTP + H2O = GDP + H(+) + phosphate; Xref=Rhea:RHEA:19669,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58189;
CC Evidence={ECO:0000305|PubMed:24095279};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19670;
CC Evidence={ECO:0000305|PubMed:24095279};
CC -!- ACTIVITY REGULATION: The activation of GTP-binding proteins is
CC generally mediated by a guanine exchange factor (GEF), while
CC inactivation through hydrolysis of bound GTP is catalyzed by a GTPase
CC activating protein (GAP) (PubMed:25936802). The GATOR1 complex
CC functions as a GAP and stimulates RRAGA GTPase activity to turn it into
CC its inactive GDP-bound form (PubMed:25936802, PubMed:23723238).
CC {ECO:0000269|PubMed:23723238, ECO:0000303|PubMed:25936802}.
CC -!- SUBUNIT: Can occur as a homodimer or as a heterodimer with RRAGC or
CC RRAGD in a sequence-independent manner; heterodimerization stabilizes
CC proteins of the heterodimer (PubMed:11073942, PubMed:20381137). In
CC complex with RRAGC, but not with RRAGB, interacts with RPTOR
CC (PubMed:18497260). The GTP-bound form of RRAGA interacts with NOL8
CC (PubMed:14660641). Component of the lysosomal folliculin complex (LFC),
CC composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound,
CC RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029,
CC PubMed:31672913). Interacts with SH3BP4; the interaction with this
CC negative regulator is most probably direct, preferentially occurs with
CC the inactive GDP-bound form of RRAGA and is negatively regulated by
CC amino acids (PubMed:22575674). The Rag heterodimer interacts with
CC SLC38A9; the probable amino acid sensor (PubMed:25561175,
CC PubMed:25567906). Interacts (inactive GDP-bound form) with RNF152;
CC stimulated by amino acid starvation (PubMed:25936802). Interacts
CC (polyubiquitinated) with the GATOR1 complex; inactivates RRAGA
CC (PubMed:25936802). Interacts (polyubiquitinated) with TSC2
CC (PubMed:25936802). Interacts with SESN1, SESN2 and SESN3
CC (PubMed:25259925). Interacts with PIP4P1 (By similarity). Interacts
CC with GPR137B (PubMed:31036939). {ECO:0000250|UniProtKB:Q80X95,
CC ECO:0000269|PubMed:11073942, ECO:0000269|PubMed:14660641,
CC ECO:0000269|PubMed:18497260, ECO:0000269|PubMed:20381137,
CC ECO:0000269|PubMed:22575674, ECO:0000269|PubMed:23723238,
CC ECO:0000269|PubMed:25259925, ECO:0000269|PubMed:25561175,
CC ECO:0000269|PubMed:25567906, ECO:0000269|PubMed:25936802,
CC ECO:0000269|PubMed:31036939, ECO:0000269|PubMed:31672913,
CC ECO:0000269|PubMed:31704029}.
CC -!- SUBUNIT: (Microbial infection) Interacts with adenovirus E3 14.7 kDa
CC protein. {ECO:0000269|PubMed:8995684}.
CC -!- INTERACTION:
CC Q7L523; P63172: DYNLT1; NbExp=3; IntAct=EBI-752376, EBI-1176455;
CC Q7L523; Q6IAA8: LAMTOR1; NbExp=11; IntAct=EBI-752376, EBI-715385;
CC Q7L523; Q9HB90: RRAGC; NbExp=20; IntAct=EBI-752376, EBI-752390;
CC Q7L523; Q9NQL2: RRAGD; NbExp=9; IntAct=EBI-752376, EBI-992949;
CC Q7L523; Q8NBW4: SLC38A9; NbExp=13; IntAct=EBI-752376, EBI-9978316;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:8995684,
CC ECO:0000269|PubMed:9394008}. Nucleus {ECO:0000269|PubMed:8995684,
CC ECO:0000269|PubMed:9394008}. Lysosome {ECO:0000269|PubMed:20381137,
CC ECO:0000269|PubMed:31036939}. Note=Predominantly cytoplasmic. May
CC shuttle between the cytoplasm and nucleus, depending on the bound
CC nucleotide state (PubMed:8995684, PubMed:9394008). Colocalizes in vivo
CC with adenovirus E3-14.7K mainly to the cytoplasm especially near the
CC nuclear membrane and in discrete foci on or near the plasma membrane
CC (PubMed:8995684). {ECO:0000269|PubMed:20381137,
CC ECO:0000269|PubMed:8995684, ECO:0000269|PubMed:9394008}.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed with highest levels of
CC expression in skeletal muscle, heart, and brain.
CC {ECO:0000269|PubMed:8995684}.
CC -!- PTM: Ubiquitinated. 'Lys-68'-linked polyubiquitination of the GDP-bound
CC inactive form of RRAGA by RNF152 is increased in response to amino acid
CC starvation. Polyubiquitination promotes interaction with the GATOR1
CC complex. This does not affect RRAGA degradation.
CC {ECO:0000269|PubMed:25936802}.
CC -!- SIMILARITY: Belongs to the GTR/RAG GTP-binding protein family.
CC {ECO:0000305}.
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DR EMBL; X90529; CAA62131.1; -; mRNA.
DR EMBL; U41654; AAB63255.1; -; mRNA.
DR EMBL; AL356000; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AK313023; BAG35858.1; -; mRNA.
DR EMBL; CH471071; EAW58653.1; -; Genomic_DNA.
DR EMBL; BC006433; AAH06433.1; -; mRNA.
DR EMBL; BC009990; AAH09990.1; -; mRNA.
DR CCDS; CCDS6488.1; -.
DR PIR; I38176; I38176.
DR RefSeq; NP_006561.1; NM_006570.4.
DR PDB; 5X6V; X-ray; 2.02 A; F=183-313.
DR PDB; 6CES; EM; 4.00 A; A=1-313.
DR PDB; 6EHR; X-ray; 2.90 A; F=183-313.
DR PDB; 6NZD; EM; 3.60 A; F=1-313.
DR PDB; 6S6A; X-ray; 2.63 A; A/B=1-313.
DR PDB; 6S6D; X-ray; 2.50 A; A/B=1-313.
DR PDB; 6SB0; EM; 5.50 A; C/I=1-313.
DR PDB; 6SB2; EM; 6.20 A; C/I=1-313.
DR PDB; 6U62; EM; 3.18 A; B=1-313.
DR PDB; 6ULG; EM; 3.31 A; F=1-313.
DR PDB; 6WJ2; EM; 3.20 A; F=1-313.
DR PDB; 6WJ3; EM; 3.90 A; F=1-313.
DR PDB; 7T3A; EM; 4.00 A; K=1-313.
DR PDB; 7T3B; EM; 3.90 A; D=1-313.
DR PDB; 7T3C; EM; 4.00 A; D/K=1-313.
DR PDBsum; 5X6V; -.
DR PDBsum; 6CES; -.
DR PDBsum; 6EHR; -.
DR PDBsum; 6NZD; -.
DR PDBsum; 6S6A; -.
DR PDBsum; 6S6D; -.
DR PDBsum; 6SB0; -.
DR PDBsum; 6SB2; -.
DR PDBsum; 6U62; -.
DR PDBsum; 6ULG; -.
DR PDBsum; 6WJ2; -.
DR PDBsum; 6WJ3; -.
DR PDBsum; 7T3A; -.
DR PDBsum; 7T3B; -.
DR PDBsum; 7T3C; -.
DR AlphaFoldDB; Q7L523; -.
DR SMR; Q7L523; -.
DR BioGRID; 115912; 46.
DR DIP; DIP-37516N; -.
DR IntAct; Q7L523; 15.
DR STRING; 9606.ENSP00000369899; -.
DR iPTMnet; Q7L523; -.
DR PhosphoSitePlus; Q7L523; -.
DR BioMuta; RRAGA; -.
DR DMDM; 74759007; -.
DR EPD; Q7L523; -.
DR jPOST; Q7L523; -.
DR MassIVE; Q7L523; -.
DR MaxQB; Q7L523; -.
DR PaxDb; Q7L523; -.
DR PeptideAtlas; Q7L523; -.
DR PRIDE; Q7L523; -.
DR ProteomicsDB; 68791; -.
DR Antibodypedia; 42790; 183 antibodies from 25 providers.
DR DNASU; 10670; -.
DR Ensembl; ENST00000380527.3; ENSP00000369899.1; ENSG00000155876.6.
DR GeneID; 10670; -.
DR KEGG; hsa:10670; -.
DR MANE-Select; ENST00000380527.3; ENSP00000369899.1; NM_006570.5; NP_006561.1.
DR UCSC; uc003znj.4; human.
DR CTD; 10670; -.
DR DisGeNET; 10670; -.
DR GeneCards; RRAGA; -.
DR HGNC; HGNC:16963; RRAGA.
DR HPA; ENSG00000155876; Low tissue specificity.
DR MIM; 612194; gene.
DR neXtProt; NX_Q7L523; -.
DR OpenTargets; ENSG00000155876; -.
DR PharmGKB; PA134980509; -.
DR VEuPathDB; HostDB:ENSG00000155876; -.
DR eggNOG; KOG3886; Eukaryota.
DR GeneTree; ENSGT00950000183031; -.
DR HOGENOM; CLU_044099_1_0_1; -.
DR InParanoid; Q7L523; -.
DR OMA; QQKDHIF; -.
DR OrthoDB; 951213at2759; -.
DR PhylomeDB; Q7L523; -.
DR TreeFam; TF300616; -.
DR PathwayCommons; Q7L523; -.
DR Reactome; R-HSA-1632852; Macroautophagy.
DR Reactome; R-HSA-165159; MTOR signalling.
DR Reactome; R-HSA-166208; mTORC1-mediated signalling.
DR Reactome; R-HSA-380972; Energy dependent regulation of mTOR by LKB1-AMPK.
DR Reactome; R-HSA-5628897; TP53 Regulates Metabolic Genes.
DR Reactome; R-HSA-8866654; E3 ubiquitin ligases ubiquitinate target proteins.
DR Reactome; R-HSA-8943724; Regulation of PTEN gene transcription.
DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1.
DR SignaLink; Q7L523; -.
DR SIGNOR; Q7L523; -.
DR BioGRID-ORCS; 10670; 330 hits in 1098 CRISPR screens.
DR ChiTaRS; RRAGA; human.
DR GeneWiki; RRAGA; -.
DR GenomeRNAi; 10670; -.
DR Pharos; Q7L523; Tbio.
DR PRO; PR:Q7L523; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q7L523; protein.
DR Bgee; ENSG00000155876; Expressed in paraflocculus and 205 other tissues.
DR Genevisible; Q7L523; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:1990131; C:Gtr1-Gtr2 GTPase complex; IBA:GO_Central.
DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; IDA:SGD.
DR GO; GO:0051219; F:phosphoprotein binding; IDA:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0008219; P:cell death; IDA:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IMP:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; IBA:GO_Central.
DR GO; GO:0010507; P:negative regulation of autophagy; IMP:UniProtKB.
DR GO; GO:0045918; P:negative regulation of cytolysis; IDA:UniProtKB.
DR GO; GO:0032008; P:positive regulation of TOR signaling; IBA:GO_Central.
DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IMP:UniProtKB.
DR GO; GO:0008104; P:protein localization; IMP:UniProtKB.
DR GO; GO:0010506; P:regulation of autophagy; IBA:GO_Central.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IDA:UniProtKB.
DR CDD; cd11384; RagA_like; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR006762; Gtr1_RagA.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR039397; RagA/B.
DR PANTHER; PTHR11259; PTHR11259; 2.
DR Pfam; PF04670; Gtr1_RagA; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Cytoplasm; GTP-binding; Host-virus interaction;
KW Hydrolase; Isopeptide bond; Lysosome; Nucleotide-binding; Nucleus;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1..313
FT /note="Ras-related GTP-binding protein A"
FT /id="PRO_0000239945"
FT BINDING 14..21
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:31672913,
FT ECO:0000269|PubMed:31704029, ECO:0007744|PDB:6NZD,
FT ECO:0007744|PDB:6ULG"
FT BINDING 62..66
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:Q00582"
FT BINDING 127..130
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:31672913,
FT ECO:0000269|PubMed:31704029, ECO:0007744|PDB:6NZD,
FT ECO:0007744|PDB:6ULG"
FT BINDING 164
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000269|PubMed:31672913,
FT ECO:0000269|PubMed:31704029, ECO:0007744|PDB:6NZD,
FT ECO:0007744|PDB:6ULG"
FT MOD_RES 309
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT CROSSLNK 142
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:25936802"
FT CROSSLNK 220
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:25936802"
FT CROSSLNK 230
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:25936802"
FT CROSSLNK 244
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:25936802"
FT MUTAGEN 21
FT /note="T->N: Reduced affinity for all nucleotides, but with
FT preferential binding of GDP over GTP."
FT /evidence="ECO:0000269|PubMed:24095279,
FT ECO:0000269|PubMed:31704029"
FT MUTAGEN 142
FT /note="K->R: Prevents RRAGA ubiquitination and alters
FT interaction and regulation by GATOR1; when associated with
FT R-220, R-230 and R-244."
FT /evidence="ECO:0000269|PubMed:25936802"
FT MUTAGEN 220
FT /note="K->R: Prevents RRAGA ubiquitination and alters
FT interaction and regulation by GATOR1; when associated with
FT R-142, R-230 and R-244."
FT /evidence="ECO:0000269|PubMed:25936802"
FT MUTAGEN 230
FT /note="K->R: Prevents RRAGA ubiquitination and alters
FT interaction and regulation by GATOR1; when associated with
FT RR-142, R-220 and R-244."
FT /evidence="ECO:0000269|PubMed:25936802"
FT MUTAGEN 244
FT /note="K->R: Prevents RRAGA ubiquitination and alters
FT interaction and regulation by GATOR1; when associated with
FT RR-142, R-220 and R-230."
FT /evidence="ECO:0000269|PubMed:25936802"
FT CONFLICT 229
FT /note="E -> G (in Ref. 2; AAB63255)"
FT /evidence="ECO:0000305"
FT CONFLICT 246
FT /note="A -> P (in Ref. 2; AAB63255)"
FT /evidence="ECO:0000305"
FT STRAND 6..13
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 16..19
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 20..28
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 33..38
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 44..53
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 56..63
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 67..73
FT /evidence="ECO:0007829|PDB:6S6D"
FT TURN 74..77
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 78..82
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 85..93
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 99..116
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 121..127
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 129..131
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 134..136
FT /evidence="ECO:0007829|PDB:6S6D"
FT HELIX 137..151
FT /evidence="ECO:0007829|PDB:6S6D"
FT TURN 152..154
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 158..161
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 164..167
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 168..178
FT /evidence="ECO:0007829|PDB:6S6D"
FT STRAND 181..183
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 188..198
FT /evidence="ECO:0007829|PDB:5X6V"
FT STRAND 201..207
FT /evidence="ECO:0007829|PDB:5X6V"
FT TURN 208..210
FT /evidence="ECO:0007829|PDB:5X6V"
FT STRAND 213..218
FT /evidence="ECO:0007829|PDB:5X6V"
FT HELIX 227..243
FT /evidence="ECO:0007829|PDB:5X6V"
FT TURN 244..246
FT /evidence="ECO:0007829|PDB:5X6V"
FT STRAND 249..256
FT /evidence="ECO:0007829|PDB:5X6V"
FT STRAND 259..264
FT /evidence="ECO:0007829|PDB:5X6V"
FT STRAND 267..277
FT /evidence="ECO:0007829|PDB:5X6V"
FT STRAND 279..281
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 283..304
FT /evidence="ECO:0007829|PDB:5X6V"
SQ SEQUENCE 313 AA; 36566 MW; B0DA1FC8FA6B766A CRC64;
MPNTAMKKKV LLMGKSGSGK TSMRSIIFAN YIARDTRRLG ATIDVEHSHV RFLGNLVLNL
WDCGGQDTFM ENYFTSQRDN IFRNVEVLIY VFDVESRELE KDMHYYQSCL EAILQNSPDA
KIFCLVHKMD LVQEDQRDLI FKEREEDLRR LSRPLECACF RTSIWDETLY KAWSSIVYQL
IPNVQQLEMN LRNFAQIIEA DEVLLFERAT FLVISHYQCK EQRDVHRFEK ISNIIKQFKL
SCSKLAASFQ SMEVRNSNFA AFIDIFTSNT YVMVVMSDPS IPSAATLINI RNARKHFEKL
ERVDGPKHSL LMR
