LTOR4_HUMAN
ID LTOR4_HUMAN Reviewed; 99 AA.
AC Q0VGL1;
DT 18-MAR-2008, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2006, sequence version 1.
DT 03-AUG-2022, entry version 130.
DE RecName: Full=Ragulator complex protein LAMTOR4;
DE AltName: Full=Late endosomal/lysosomal adaptor and MAPK and MTOR activator 4;
DE Contains:
DE RecName: Full=Ragulator complex protein LAMTOR4, N-terminally processed;
GN Name=LAMTOR4; Synonyms=C7orf59;
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 [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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Skin;
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 [3]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [4]
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 [5]
RP FUNCTION IN MTORC1 SIGNALING, IDENTIFICATION IN RAGULATOR COMPLEX,
RP INTERACTION WITH MTORC1 COMPLEX AND RAG GTPASES, AND SUBCELLULAR LOCATION.
RX PubMed=22980980; DOI=10.1016/j.cell.2012.07.032;
RA Bar-Peled L., Schweitzer L.D., Zoncu R., Sabatini D.M.;
RT "Ragulator is a GEF for the Rag GTPases that signal amino acid levels to
RT mTORC1.";
RL Cell 150:1196-1208(2012).
RN [6]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1 AND THR-2, CLEAVAGE OF
RP INITIATOR METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [7]
RP IDENTIFICATION BY 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 [8]
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 [9]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-2, CLEAVAGE OF INITIATOR
RP METHIONINE [LARGE SCALE ANALYSIS], AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [10]
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 [11] {ECO:0007744|PDB:6ULG}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.31 ANGSTROMS) IN COMPLEX WITH FLCN;
RP FNIP2; RRAGA; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3 AND LAMTOR5, AND
RP IDENTIFICATION IN THE LFC COMPLEX.
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 [12] {ECO:0007744|PDB:6NZD}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) IN COMPLEX WITH FLCN;
RP FNIP2; RRAGA; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3 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: As part of the Ragulator complex it is involved in amino acid
CC sensing and activation of mTORC1, a signaling complex promoting cell
CC growth in response to growth factors, energy levels, and amino acids.
CC Activated by amino acids through a mechanism involving the lysosomal V-
CC ATPase, the Ragulator functions as a guanine nucleotide exchange factor
CC activating the small GTPases Rag. Activated Ragulator and Rag GTPases
CC function as a scaffold recruiting mTORC1 to lysosomes where it is in
CC turn activated. {ECO:0000269|PubMed:22980980}.
CC -!- SUBUNIT: Part of the Ragulator complex composed of LAMTOR1, LAMTOR2,
CC LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:22980980). LAMTOR4 and LAMTOR5
CC form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2,
CC LAMTOR3 heterodimer (PubMed:22980980). The Ragulator complex interacts
CC with both the mTORC1 complex and heterodimers constituted of the Rag
CC GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid
CC availability (PubMed:22980980). The Ragulator complex interacts with
CC SLC38A9; the probable amino acid sensor (PubMed:25561175,
CC PubMed:25567906). 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). {ECO:0000269|PubMed:22980980,
CC ECO:0000269|PubMed:25561175, ECO:0000269|PubMed:25567906,
CC ECO:0000269|PubMed:31672913, ECO:0000269|PubMed:31704029}.
CC -!- INTERACTION:
CC Q0VGL1; A0A0C4DGV4: LAMTOR5; NbExp=12; IntAct=EBI-5658976, EBI-10173304;
CC Q0VGL1; O43504: LAMTOR5; NbExp=5; IntAct=EBI-5658976, EBI-713382;
CC Q0VGL1; Q8NBW4: SLC38A9; NbExp=4; IntAct=EBI-5658976, EBI-9978316;
CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:22980980}.
CC -!- SIMILARITY: Belongs to the LAMTOR4 family. {ECO:0000305}.
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DR EMBL; CH471091; EAW76585.1; -; Genomic_DNA.
DR EMBL; BC063401; AAH63401.1; -; mRNA.
DR EMBL; BC105609; AAI05610.1; -; mRNA.
DR EMBL; BC130553; AAI30554.1; -; mRNA.
DR EMBL; BC130559; AAI30560.1; -; mRNA.
DR CCDS; CCDS34702.1; -.
DR RefSeq; NP_001008396.1; NM_001008395.3.
DR RefSeq; XP_016867687.1; XM_017012198.1.
DR PDB; 5VOK; X-ray; 2.89 A; B/D/F/H=1-99.
DR PDB; 5X6U; X-ray; 2.40 A; D=1-99.
DR PDB; 5X6V; X-ray; 2.02 A; D=1-99.
DR PDB; 5Y38; X-ray; 2.80 A; B=1-99.
DR PDB; 5Y39; X-ray; 2.65 A; D/I=1-99.
DR PDB; 5Y3A; X-ray; 2.90 A; D/I=1-99.
DR PDB; 5YK5; X-ray; 2.03 A; A=9-92, C=9-91.
DR PDB; 6B9X; X-ray; 1.42 A; D=1-99.
DR PDB; 6EHP; X-ray; 2.30 A; D=1-99.
DR PDB; 6EHR; X-ray; 2.90 A; D=1-99.
DR PDB; 6NZD; EM; 3.60 A; D=1-99.
DR PDB; 6U62; EM; 3.18 A; G=2-99.
DR PDB; 6ULG; EM; 3.31 A; D=1-99.
DR PDB; 6WJ2; EM; 3.20 A; D=1-99.
DR PDB; 6WJ3; EM; 3.90 A; D=1-99.
DR PDB; 7T3A; EM; 4.00 A; P=1-99.
DR PDB; 7T3B; EM; 3.90 A; I=1-99.
DR PDB; 7T3C; EM; 4.00 A; I/P=1-99.
DR PDBsum; 5VOK; -.
DR PDBsum; 5X6U; -.
DR PDBsum; 5X6V; -.
DR PDBsum; 5Y38; -.
DR PDBsum; 5Y39; -.
DR PDBsum; 5Y3A; -.
DR PDBsum; 5YK5; -.
DR PDBsum; 6B9X; -.
DR PDBsum; 6EHP; -.
DR PDBsum; 6EHR; -.
DR PDBsum; 6NZD; -.
DR PDBsum; 6U62; -.
DR PDBsum; 6ULG; -.
DR PDBsum; 6WJ2; -.
DR PDBsum; 6WJ3; -.
DR PDBsum; 7T3A; -.
DR PDBsum; 7T3B; -.
DR PDBsum; 7T3C; -.
DR AlphaFoldDB; Q0VGL1; -.
DR SMR; Q0VGL1; -.
DR BioGRID; 133178; 42.
DR ComplexPortal; CPX-4741; Ragulator complex.
DR CORUM; Q0VGL1; -.
DR DIP; DIP-61481N; -.
DR IntAct; Q0VGL1; 20.
DR STRING; 9606.ENSP00000343118; -.
DR iPTMnet; Q0VGL1; -.
DR PhosphoSitePlus; Q0VGL1; -.
DR SwissPalm; Q0VGL1; -.
DR BioMuta; LAMTOR4; -.
DR DMDM; 121940512; -.
DR EPD; Q0VGL1; -.
DR jPOST; Q0VGL1; -.
DR MassIVE; Q0VGL1; -.
DR MaxQB; Q0VGL1; -.
DR PaxDb; Q0VGL1; -.
DR PeptideAtlas; Q0VGL1; -.
DR PRIDE; Q0VGL1; -.
DR ProteomicsDB; 58845; -.
DR TopDownProteomics; Q0VGL1; -.
DR Antibodypedia; 16403; 66 antibodies from 16 providers.
DR DNASU; 389541; -.
DR Ensembl; ENST00000341942.10; ENSP00000343118.5; ENSG00000188186.11.
DR GeneID; 389541; -.
DR KEGG; hsa:389541; -.
DR MANE-Select; ENST00000341942.10; ENSP00000343118.5; NM_001008395.4; NP_001008396.1.
DR UCSC; uc003utq.3; human.
DR CTD; 389541; -.
DR GeneCards; LAMTOR4; -.
DR HGNC; HGNC:33772; LAMTOR4.
DR HPA; ENSG00000188186; Low tissue specificity.
DR MIM; 618834; gene.
DR neXtProt; NX_Q0VGL1; -.
DR OpenTargets; ENSG00000188186; -.
DR PharmGKB; PA162380687; -.
DR VEuPathDB; HostDB:ENSG00000188186; -.
DR eggNOG; ENOG502S3B2; Eukaryota.
DR GeneTree; ENSGT00390000016053; -.
DR HOGENOM; CLU_137556_1_0_1; -.
DR InParanoid; Q0VGL1; -.
DR OMA; CRFRLHG; -.
DR OrthoDB; 1589714at2759; -.
DR PhylomeDB; Q0VGL1; -.
DR TreeFam; TF324352; -.
DR PathwayCommons; Q0VGL1; -.
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-8943724; Regulation of PTEN gene transcription.
DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1.
DR SignaLink; Q0VGL1; -.
DR SIGNOR; Q0VGL1; -.
DR BioGRID-ORCS; 389541; 333 hits in 1079 CRISPR screens.
DR ChiTaRS; LAMTOR4; human.
DR GenomeRNAi; 389541; -.
DR Pharos; Q0VGL1; Tdark.
DR PRO; PR:Q0VGL1; -.
DR Proteomes; UP000005640; Chromosome 7.
DR RNAct; Q0VGL1; protein.
DR Bgee; ENSG00000188186; Expressed in skin of abdomen and 181 other tissues.
DR ExpressionAtlas; Q0VGL1; baseline and differential.
DR Genevisible; Q0VGL1; HS.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0031902; C:late endosome membrane; IC:ComplexPortal.
DR GO; GO:0005765; C:lysosomal membrane; TAS:Reactome.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0071986; C:Ragulator complex; IDA:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IDA:ComplexPortal.
DR GO; GO:0032008; P:positive regulation of TOR signaling; IMP:UniProtKB.
DR GO; GO:0061462; P:protein localization to lysosome; IMP:UniProtKB.
DR GO; GO:0050790; P:regulation of catalytic activity; IEA:GOC.
DR GO; GO:0008361; P:regulation of cell size; IMP:UniProtKB.
DR GO; GO:0038202; P:TORC1 signaling; IC:ComplexPortal.
DR InterPro; IPR034601; LAMTOR4.
DR PANTHER; PTHR33967; PTHR33967; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Lysosome; Reference proteome.
FT CHAIN 1..99
FT /note="Ragulator complex protein LAMTOR4"
FT /id="PRO_0000325841"
FT INIT_MET 1
FT /note="Removed; alternate"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378, ECO:0007744|PubMed:25944712"
FT CHAIN 2..99
FT /note="Ragulator complex protein LAMTOR4, N-terminally
FT processed"
FT /id="PRO_0000424498"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT MOD_RES 2
FT /note="N-acetylthreonine; in Ragulator complex protein
FT LAMTOR4, N-terminally processed"
FT /evidence="ECO:0007744|PubMed:19413330,
FT ECO:0007744|PubMed:22814378, ECO:0007744|PubMed:25944712"
FT HELIX 4..10
FT /evidence="ECO:0007829|PDB:6B9X"
FT STRAND 15..22
FT /evidence="ECO:0007829|PDB:6B9X"
FT STRAND 25..31
FT /evidence="ECO:0007829|PDB:6B9X"
FT TURN 32..35
FT /evidence="ECO:0007829|PDB:6B9X"
FT HELIX 37..52
FT /evidence="ECO:0007829|PDB:6B9X"
FT STRAND 56..58
FT /evidence="ECO:0007829|PDB:5VOK"
FT STRAND 59..62
FT /evidence="ECO:0007829|PDB:6B9X"
FT STRAND 64..69
FT /evidence="ECO:0007829|PDB:6B9X"
FT STRAND 71..80
FT /evidence="ECO:0007829|PDB:6B9X"
FT STRAND 83..90
FT /evidence="ECO:0007829|PDB:6B9X"
SQ SEQUENCE 99 AA; 10741 MW; 0FB3D6613F295DEB CRC64;
MTSALTQGLE RIPDQLGYLV LSEGAVLASS GDLENDEQAA SAISELVSTA CGFRLHRGMN
VPFKRLSVVF GEHTLLVTVS GQRVFVVKRQ NRGREPIDV
