NPRL3_HUMAN
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 03-AUG-2022, entry version 146.
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 Q12980; Q8WTW4: NPRL2; NbExp=6; IntAct=EBI-2650314, EBI-1043552;
CC Q12980; 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 variants 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 PDB; 7T3A; EM; 4.00 A; C=1-569.
DR PDB; 7T3B; EM; 3.90 A; C=1-569.
DR PDB; 7T3C; EM; 4.00 A; C=1-569.
DR PDBsum; 6CES; -.
DR PDBsum; 6CET; -.
DR PDBsum; 7T3A; -.
DR PDBsum; 7T3B; -.
DR PDBsum; 7T3C; -.
DR AlphaFoldDB; Q12980; -.
DR SMR; Q12980; -.
DR BioGRID; 113796; 112.
DR ComplexPortal; CPX-6226; GATOR1 complex.
DR CORUM; Q12980; -.
DR DIP; DIP-62051N; -.
DR IntAct; Q12980; 14.
DR STRING; 9606.ENSP00000483814; -.
DR GlyConnect; 2060; 1 N-Linked glycan (1 site).
DR GlyGen; Q12980; 1 site, 2 N-linked glycans (1 site).
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 Antibodypedia; 1565; 86 antibodies from 27 providers.
DR DNASU; 8131; -.
DR Ensembl; ENST00000611875.5; ENSP00000478273.1; ENSG00000103148.17.
DR GeneID; 8131; -.
DR KEGG; hsa:8131; -.
DR MANE-Select; ENST00000611875.5; ENSP00000478273.1; NM_001077350.3; NP_001070818.1.
DR UCSC; uc032dmr.2; human.
DR CTD; 8131; -.
DR DisGeNET; 8131; -.
DR GeneCards; NPRL3; -.
DR HGNC; HGNC:14124; NPRL3.
DR HPA; ENSG00000103148; Low tissue specificity.
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 VEuPathDB; HostDB:ENSG00000103148; -.
DR eggNOG; KOG3830; Eukaryota.
DR GeneTree; ENSGT00390000015916; -.
DR HOGENOM; CLU_014030_1_0_1; -.
DR InParanoid; Q12980; -.
DR OMA; CLPQKVH; -.
DR OrthoDB; 628619at2759; -.
DR PhylomeDB; Q12980; -.
DR TreeFam; TF105965; -.
DR PathwayCommons; Q12980; -.
DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1.
DR SignaLink; Q12980; -.
DR SIGNOR; Q12980; -.
DR BioGRID-ORCS; 8131; 39 hits in 268 CRISPR screens.
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 193 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:1904262; P:negative regulation of TORC1 signaling; IBA:GO_Central.
DR GO; GO:0010508; P:positive regulation of autophagy; 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 variant; Epilepsy; GTPase activation; Lysosome;
KW Membrane; Phosphoprotein; Reference proteome.
FT CHAIN 1..569
FT /note="GATOR complex protein NPRL3"
FT /id="PRO_0000220638"
FT REGION 27..60
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 416..477
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 31..47
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 436..477
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 476
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|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
