ID   NPRL3_HUMAN             Reviewed;         569 AA.
AC   Q12980; D3DU40; Q1W6H0; Q4TT56; Q92469;
DT   26-SEP-2001, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   26-FEB-2020, entry version 135.
DE   RecName: Full=GATOR complex protein NPRL3 {ECO:0000305};
DE   AltName: Full=-14 gene protein {ECO:0000303|PubMed:8575760};
DE   AltName: Full=Alpha-globin regulatory element-containing gene protein {ECO:0000303|PubMed:8575760};
DE   AltName: Full=Nitrogen permease regulator 3-like protein {ECO:0000312|HGNC:HGNC:14124};
DE   AltName: Full=Protein CGTHBA;
GN   Name=NPRL3 {ECO:0000312|HGNC:HGNC:14124};
GN   Synonyms=C16orf35 {ECO:0000312|HGNC:HGNC:14124}, CGTHBA,
GN   MARE {ECO:0000305|PubMed:8575760};
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].
RX   PubMed=8575760; DOI=10.1006/geno.1995.9951;
RA   Vyas P., Vickers M.A., Picketts D.J., Higgs D.;
RT   "Conservation of position and sequence of a novel, widely expressed gene
RT   containing the major human alpha-globin regulatory element.";
RL   Genomics 29:679-689(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=16728641; DOI=10.1126/science.1126431;
RA   De Gobbi M., Viprakasit V., Hughes J.R., Fisher C., Buckle V.J., Ayyub H.,
RA   Gibbons R.J., Vernimmen D., Yoshinaga Y., de Jong P., Cheng J.-F.,
RA   Rubin E.M., Wood W.G., Bowden D., Higgs D.R.;
RT   "A regulatory SNP causes a human genetic disease by creating a new
RT   transcriptional promoter.";
RL   Science 312:1215-1217(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=15616553; DOI=10.1038/nature03187;
RA   Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G.,
RA   Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E.,
RA   Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M.,
RA   Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C.,
RA   Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M.,
RA   Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M.,
RA   Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D.,
RA   Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L.,
RA   Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E.,
RA   Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H.,
RA   Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y.,
RA   Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA   Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA   Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S.,
RA   Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A.,
RA   Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M.,
RA   Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H.,
RA   Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A.,
RA   Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J.,
RA   DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J.,
RA   Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M.,
RA   Myers R.M., Rubin E.M., Pennacchio L.A.;
RT   "The sequence and analysis of duplication-rich human chromosome 16.";
RL   Nature 432:988-994(2004).
RN   [4]
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   [5]
RP   INTERACTION WITH NPRL2.
RX   PubMed=19521502; DOI=10.1371/journal.pgen.1000515;
RA   Neklesa T.K., Davis R.W.;
RT   "A genome-wide screen for regulators of TORC1 in response to amino acid
RT   starvation reveals a conserved Npr2/3 complex.";
RL   PLoS Genet. 5:E1000515-E1000515(2009).
RN   [6]
RP   FUNCTION, IDENTIFICATION IN GATOR COMPLEX, AND INTERACTION WITH RRAG
RP   PROTEINS.
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   [7]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-476, AND IDENTIFICATION BY
RP   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   [8]
RP   SUBCELLULAR LOCATION.
RX   PubMed=28199306; DOI=10.1038/nature21423;
RA   Wolfson R.L., Chantranupong L., Wyant G.A., Gu X., Orozco J.M., Shen K.,
RA   Condon K.J., Petri S., Kedir J., Scaria S.M., Abu-Remaileh M.,
RA   Frankel W.N., Sabatini D.M.;
RT   "KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to
RT   regulate mTORC1.";
RL   Nature 543:438-442(2017).
RN   [9]
RP   INVOLVEMENT IN FFEVF3, VARIANTS FFEVF3 GLN-92 AND LYS-249, AND TISSUE
RP   SPECIFICITY.
RX   PubMed=26505888; DOI=10.1002/ana.24547;
RG   Epilepsy Electroclinical Study Group;
RA   Ricos M.G., Hodgson B.L., Pippucci T., Saidin A., Ong Y.S., Heron S.E.,
RA   Licchetta L., Bisulli F., Bayly M.A., Hughes J., Baldassari S., Palombo F.,
RA   Santucci M., Meletti S., Berkovic S.F., Rubboli G., Thomas P.Q.,
RA   Scheffer I.E., Tinuper P., Geoghegan J., Schreiber A.W., Dibbens L.M.;
RT   "Mutations in the mammalian target of rapamycin pathway regulators NPRL2
RT   and NPRL3 cause focal epilepsy.";
RL   Ann. Neurol. 79:120-131(2016).
RN   [10]
RP   INVOLVEMENT IN FFEVF3, AND VARIANT FFEVF3 GLN-92.
RX   PubMed=26285051; DOI=10.1002/ana.24502;
RA   Sim J.C., Scerri T., Fanjul-Fernandez M., Riseley J.R., Gillies G.,
RA   Pope K., van Roozendaal H., Heng J.I., Mandelstam S.A., McGillivray G.,
RA   MacGregor D., Kannan L., Maixner W., Harvey A.S., Amor D.J.,
RA   Delatycki M.B., Crino P.B., Bahlo M., Lockhart P.J., Leventer R.J.;
RT   "Familial cortical dysplasia caused by mutation in the mammalian target of
RT   rapamycin regulator NPRL3.";
RL   Ann. Neurol. 79:132-137(2016).
RN   [11]
RP   INVOLVEMENT IN FFEVF3, VARIANT FFEVF3 LYS-249, AND TISSUE SPECIFICITY.
RX   PubMed=27173016; DOI=10.1111/epi.13391;
RA   Weckhuysen S., Marsan E., Lambrecq V., Marchal C., Morin-Brureau M.,
RA   An-Gourfinkel I., Baulac M., Fohlen M., Kallay Zetchi C., Seeck M.,
RA   de la Grange P., Dermaut B., Meurs A., Thomas P., Chassoux F., Leguern E.,
RA   Picard F., Baulac S.;
RT   "Involvement of GATOR complex genes in familial focal epilepsies and focal
RT   cortical dysplasia.";
RL   Epilepsia 57:994-1003(2016).
CC   -!- FUNCTION: As a component of the GATOR1 complex functions as an
CC       inhibitor of the amino acid-sensing branch of the TORC1 pathway. The
CC       GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB
CC       within RRAGC-containing heterodimers, thereby deactivating RRAGs,
CC       releasing mTORC1 from lysosomal surface and inhibiting mTORC1
CC       signaling. The GATOR1 complex is negatively regulated by GATOR2 the
CC       other GATOR subcomplex in this amino acid-sensing branch of the TORC1
CC       pathway. {ECO:0000269|PubMed:23723238}.
CC   -!- SUBUNIT: Forms a heterodimer with NPRL2. Within the GATOR complex,
CC       component of the GATOR1 subcomplex, made of DEPDC5, NPRL2 and NPRL3.
CC       GATOR1 mediates the strong interaction of the GATOR complex with
CC       RRAGA/RRAGC and RRAGB/RRAGC heterodimers.
CC       {ECO:0000269|PubMed:23723238}.
CC   -!- INTERACTION:
CC       Q8WTW4:NPRL2; NbExp=6; IntAct=EBI-2650314, EBI-1043552;
CC       Q5T011:SZT2; NbExp=5; IntAct=EBI-2650314, EBI-10749411;
CC   -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:28199306}.
CC       Note=Localization to lysosomes is amino acid-independent.
CC       {ECO:0000269|PubMed:28199306}.
CC   -!- TISSUE SPECIFICITY: Widely expressed. Expressed in the frontal lobe
CC       cortex as well as in the temporal, parietal, and occipital lobes
CC       (PubMed:27173016, PubMed:26505888). {ECO:0000269|PubMed:26505888,
CC       ECO:0000269|PubMed:27173016}.
CC   -!- DISEASE: Note=Inactivating mutations and truncating deletions in the
CC       genes encoding GATOR1 proteins are detected in glioblastoma and ovarian
CC       tumors and are associated with loss of heterozygosity events.
CC       Inactivation of GATOR1 proteins promotes constitutive localization of
CC       mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation
CC       following amino acid withdrawal (PubMed:23723238).
CC       {ECO:0000269|PubMed:23723238}.
CC   -!- DISEASE: Epilepsy, familial focal, with variable foci 3 (FFEVF3)
CC       [MIM:617118]: An autosomal dominant form of epilepsy characterized by
CC       focal seizures arising from different cortical regions, including the
CC       temporal, frontal, parietal, and occipital lobes. Seizure types
CC       commonly include temporal lobe epilepsy, frontal lobe epilepsy, and
CC       nocturnal frontal lobe epilepsy. Some patients may have intellectual
CC       disability or autism spectrum disorders. Seizure onset usually occurs
CC       in the first or second decades, although later onset has been reported,
CC       and there is phenotypic variability within families. A subset of
CC       patients have structural brain abnormalities. Penetrance of the
CC       disorder is incomplete. {ECO:0000269|PubMed:26285051,
CC       ECO:0000269|PubMed:26505888, ECO:0000269|PubMed:27173016}. Note=The
CC       disease is caused by mutations affecting the gene represented in this
CC       entry.
CC   -!- SIMILARITY: Belongs to the NPR3 family. {ECO:0000305}.
CC   -!- CAUTION: Ser-489 is missing in the human genome assembly but is present
CC       in all available mRNAs and ESTs. {ECO:0000305}.
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DR   EMBL; X90857; CAA62368.1; -; mRNA.
DR   EMBL; DQ431198; ABD95907.1; -; Genomic_DNA.
DR   EMBL; Z69666; CAI94885.1; -; Genomic_DNA.
DR   EMBL; Z69720; CAI94885.1; JOINED; Genomic_DNA.
DR   EMBL; Z84722; CAI94885.1; JOINED; Genomic_DNA.
DR   EMBL; Z69720; CAI95611.1; -; Genomic_DNA.
DR   EMBL; Z69666; CAI95611.1; JOINED; Genomic_DNA.
DR   EMBL; Z84722; CAI95611.1; JOINED; Genomic_DNA.
DR   EMBL; CH471112; EAW85865.1; -; Genomic_DNA.
DR   EMBL; CH471112; EAW85867.1; -; Genomic_DNA.
DR   CCDS; CCDS73795.1; -.
DR   RefSeq; NP_001070818.1; NM_001077350.2.
DR   PDB; 6CES; EM; 4.00 A; M=1-569.
DR   PDB; 6CET; EM; 4.40 A; M=1-569.
DR   PDBsum; 6CES; -.
DR   PDBsum; 6CET; -.
DR   SMR; Q12980; -.
DR   BioGrid; 113796; 59.
DR   CORUM; Q12980; -.
DR   DIP; DIP-62051N; -.
DR   IntAct; Q12980; 14.
DR   STRING; 9606.ENSP00000483814; -.
DR   GlyConnect; 2060; -.
DR   iPTMnet; Q12980; -.
DR   PhosphoSitePlus; Q12980; -.
DR   BioMuta; NPRL3; -.
DR   DMDM; 18202492; -.
DR   EPD; Q12980; -.
DR   jPOST; Q12980; -.
DR   MassIVE; Q12980; -.
DR   MaxQB; Q12980; -.
DR   PaxDb; Q12980; -.
DR   PeptideAtlas; Q12980; -.
DR   PRIDE; Q12980; -.
DR   ProteomicsDB; 59074; -.
DR   DNASU; 8131; -.
DR   Ensembl; ENST00000611875; ENSP00000478273; ENSG00000103148.
DR   Ensembl; ENST00000620134; ENSP00000483814; ENSG00000103148.
DR   GeneID; 8131; -.
DR   KEGG; hsa:8131; -.
DR   UCSC; uc032dmr.2; human.
DR   CTD; 8131; -.
DR   DisGeNET; 8131; -.
DR   GeneCards; NPRL3; -.
DR   HGNC; HGNC:14124; NPRL3.
DR   HPA; HPA011741; -.
DR   MalaCards; NPRL3; -.
DR   MIM; 600928; gene.
DR   MIM; 617118; phenotype.
DR   neXtProt; NX_Q12980; -.
DR   OpenTargets; ENSG00000103148; -.
DR   Orphanet; 98820; Familial focal epilepsy with variable foci.
DR   PharmGKB; PA25550; -.
DR   eggNOG; KOG3830; Eukaryota.
DR   eggNOG; ENOG410XP4E; LUCA.
DR   GeneTree; ENSGT00390000015916; -.
DR   HOGENOM; CLU_014030_1_0_1; -.
DR   InParanoid; Q12980; -.
DR   KO; K20406; -.
DR   OMA; CLPQKVH; -.
DR   OrthoDB; 628619at2759; -.
DR   PhylomeDB; Q12980; -.
DR   TreeFam; TF105965; -.
DR   Reactome; R-HSA-9639288; Amino acids regulate mTORC1.
DR   SIGNOR; Q12980; -.
DR   ChiTaRS; NPRL3; human.
DR   GenomeRNAi; 8131; -.
DR   Pharos; Q12980; Tbio.
DR   PRO; PR:Q12980; -.
DR   Proteomes; UP000005640; Chromosome 16.
DR   RNAct; Q12980; protein.
DR   Bgee; ENSG00000103148; Expressed in blood and 214 other tissues.
DR   ExpressionAtlas; Q12980; baseline and differential.
DR   Genevisible; Q12980; HS.
DR   GO; GO:1990130; C:GATOR1 complex; IDA:SGD.
DR   GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR   GO; GO:0005096; F:GTPase activator activity; IEA:UniProtKB-KW.
DR   GO; GO:0035909; P:aorta morphogenesis; IEA:Ensembl.
DR   GO; GO:0048738; P:cardiac muscle tissue development; IEA:Ensembl.
DR   GO; GO:0034198; P:cellular response to amino acid starvation; IMP:UniProtKB.
DR   GO; GO:0032007; P:negative regulation of TOR signaling; IMP:SGD.
DR   GO; GO:2000785; P:regulation of autophagosome assembly; IBA:GO_Central.
DR   GO; GO:0060021; P:roof of mouth development; IEA:Ensembl.
DR   GO; GO:0038202; P:TORC1 signaling; IBA:GO_Central.
DR   GO; GO:0003281; P:ventricular septum development; IEA:Ensembl.
DR   InterPro; IPR005365; Npr3.
DR   PANTHER; PTHR13153; PTHR13153; 1.
DR   Pfam; PF03666; NPR3; 2.
PE   1: Evidence at protein level;
KW   3D-structure; Disease mutation; Epilepsy; GTPase activation; Lysosome;
KW   Membrane; Phosphoprotein; Reference proteome.
FT   CHAIN           1..569
FT                   /note="GATOR complex protein NPRL3"
FT                   /id="PRO_0000220638"
FT   MOD_RES         476
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000244|PubMed:24275569"
FT   VARIANT         92
FT                   /note="R -> Q (in FFEVF3; unknown pathological
FT                   significance; dbSNP:rs367729589)"
FT                   /evidence="ECO:0000269|PubMed:26285051,
FT                   ECO:0000269|PubMed:26505888"
FT                   /id="VAR_077126"
FT   VARIANT         249
FT                   /note="E -> K (in FFEVF3; unknown pathological
FT                   significance; dbSNP:rs200041907)"
FT                   /evidence="ECO:0000269|PubMed:26505888,
FT                   ECO:0000269|PubMed:27173016"
FT                   /id="VAR_077127"
FT   CONFLICT        489
FT                   /note="Missing (in Ref. 2; CAI94885/CAI95611)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   569 AA;  63605 MW;  44BEF42AA7F2841D CRC64;
     MRDNTSPISV ILVSSGSRGN KLLFRYPFQR SQEHPASQTS KPRSRYAASN TGDHADEQDG
     DSRFSDVILA TILATKSEMC GQKFELKIDN VRFVGHPTLL QHALGQISKT DPSPKREAPT
     MILFNVVFAL RANADPSVIN CLHNLSRRIA TVLQHEERRC QYLTREAKLI LALQDEVSAM
     ADGNEGPQSP FHHILPKCKL ARDLKEAYDS LCTSGVVRLH INSWLEVSFC LPHKIHYAAS
     SLIPPEAIER SLKAIRPYHA LLLLSDEKSL LGELPIDCSP ALVRVIKTTS AVKNLQQLAQ
     DADLALLQVF QLAAHLVYWG KAIIIYPLCE NNVYMLSPNA SVCLYSPLAE QFSHQFPSHD
     LPSVLAKFSL PVSLSEFRNP LAPAVQETQL IQMVVWMLQR RLLIQLHTYV CLMASPSEEE
     PRPREDDVPF TARVGGRSLS TPNALSFGSP TSSDDMTLTS PSMDNSSAEL LPSGDSPLNQ
     RMTENLLASL SEHERAAILS VPAAQNPEDL RMFARLLHYF RGRHHLEEIM YNENTRRSQL
     LMLFDKFRSV LVVTTHEDPV IAVFQALLP
//