ID S38A9_HUMAN Reviewed; 561 AA.
AC Q8NBW4; A0A0A8K8P2; B3KXV1; B7Z7D0; Q0P5S0; Q6MZJ8;
DT 08-APR-2008, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 05-FEB-2025, entry version 162.
DE RecName: Full=Neutral amino acid transporter 9 {ECO:0000305};
DE AltName: Full=Solute carrier family 38 member 9 {ECO:0000312|HGNC:HGNC:26907};
DE AltName: Full=Up-regulated in lung cancer 11 {ECO:0000303|Ref.2};
GN Name=SLC38A9 {ECO:0000312|HGNC:HGNC:26907};
GN Synonyms=URLC11 {ECO:0000303|Ref.2};
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 MRNA] (ISOFORMS 1; 3 AND 4), AND VARIANT
RP THR-182.
RC TISSUE=Placenta, and 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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT THR-182.
RA Daigo Y., Nakamura Y.;
RT "Isolation and characterization of novel human genes, which are up-
RT regulated in lung cancer.";
RL Submitted (JAN-2015) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A.,
RA Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R.,
RA Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L.,
RA Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N.,
RA Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J.,
RA Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A.,
RA Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT THR-182.
RC TISSUE=Testis;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 173-561 (ISOFORM 2), AND VARIANT
RP THR-182.
RC TISSUE=Fetal kidney;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D.,
RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A.,
RA Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [8]
RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, SUBCELLULAR LOCATION,
RP IDENTIFICATION BY MASS SPECTROMETRY, SUBUNIT, GLYCOSYLATION, AND
RP MUTAGENESIS OF 38-ARG--PHE-40; 70-TYR--ARG-73; 85-PRO--HIS-87;
RP 98-TYR--LEU-101 AND ASN-128.
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 FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, SUBUNIT,
RP GLYCOSYLATION, AND MUTAGENESIS OF HIS-60; ILE-68; TYR-71; LEU-74; PRO-85
RP AND PRO-90.
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 [10]
RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, SUBCELLULAR LOCATION, SUBUNIT, AND MUTAGENESIS OF ILE-68 AND
RP THR-133.
RX PubMed=29053970; DOI=10.1016/j.cell.2017.09.046;
RA Wyant G.A., Abu-Remaileh M., Wolfson R.L., Chen W.W., Freinkman E.,
RA Danai L.V., Vander Heiden M.G., Sabatini D.M.;
RT "mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from
RT Lysosomes and Use Protein as a Nutrient.";
RL Cell 171:642-654(2017).
RN [11]
RP FUNCTION, MUTAGENESIS OF PHE-449 AND TYR-460, AND INTERACTION WITH NPC1;
RP LAMTOR1 AND THE RAG GTPASES HETERODIMER (RRAGA AND RRAGC).
RX PubMed=28336668; DOI=10.1126/science.aag1417;
RA Castellano B.M., Thelen A.M., Moldavski O., Feltes M., van der Welle R.E.,
RA Mydock-McGrane L., Jiang X., van Eijkeren R.J., Davis O.B., Louie S.M.,
RA Perera R.M., Covey D.F., Nomura D.K., Ory D.S., Zoncu R.;
RT "Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1
RT signaling complex.";
RL Science 355:1306-1311(2017).
RN [12]
RP SUBUNIT, DOMAIN, AND FUNCTION.
RX PubMed=30181260; DOI=10.1073/pnas.1811727115;
RA Shen K., Sabatini D.M.;
RT "Ragulator and SLC38A9 activate the Rag GTPases through noncanonical GEF
RT mechanisms.";
RL Proc. Natl. Acad. Sci. U.S.A. 115:9545-9550(2018).
RN [13]
RP FUNCTION, TRANSPORTER ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL
RP PROPERTIES, AND MUTAGENESIS OF PHE-449; THR-453 AND TYR-460.
RX PubMed=31295473; DOI=10.1016/j.bbamem.2019.07.006;
RA Scalise M., Galluccio M., Pochini L., Cosco J., Trotta M., Rebsamen M.,
RA Superti-Furga G., Indiveri C.;
RT "Insights into the transport side of the human SLC38A9 transceptor.";
RL Biochim. Biophys. Acta 1861:1558-1567(2019).
RN [14]
RP INTERACTION WITH TM4SF5, AND SUBCELLULAR LOCATION.
RX PubMed=30956113; DOI=10.1016/j.cmet.2019.03.005;
RA Jung J.W., Macalino S.J.Y., Cui M., Kim J.E., Kim H.J., Song D.G.,
RA Nam S.H., Kim S., Choi S., Lee J.W.;
RT "Transmembrane 4 L six family member 5 senses arginine for mTORC1
RT signaling.";
RL Cell Metab. 29:1306-1319(2019).
RN [15] {ECO:0007744|PDB:6WJ2, ECO:0007744|PDB:6WJ3}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.20 ANGSTROMS) OF 1-119 IN COMPLEX WITH
RP THE RAGULATOR COMPLEX AND THE RAG GTPASES HETERODIMER (RRAGA AND RRAGC),
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF HIS-60; ILE-68; TYR-71 AND LEU-74.
RX PubMed=32868926; DOI=10.1038/s41594-020-0490-9;
RA Fromm S.A., Lawrence R.E., Hurley J.H.;
RT "Structural mechanism for amino acid-dependent Rag GTPase nucleotide state
RT switching by SLC38A9.";
RL Nat. Struct. Mol. Biol. 27:1017-1023(2020).
RN [16] {ECO:0007744|PDB:8DHB}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.53 ANGSTROMS) IN COMPLEX WITH RRAGA;
RP RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4; LAMTOR5; FNIP2 AND FLCN.
RX PubMed=36103527; DOI=10.1126/sciadv.add2926;
RA Jansen R.M., Peruzzo R., Fromm S.A., Yokom A.L., Zoncu R., Hurley J.H.;
RT "Structural basis for FLCN RagC GAP activation in MiT-TFE substrate-
RT selective mTORC1 regulation.";
RL Sci. Adv. 8:eadd2926-eadd2926(2022).
CC -!- FUNCTION: Lysosomal amino acid transporter involved in the activation
CC of mTORC1 in response to amino acid levels (PubMed:25561175,
CC PubMed:25567906, PubMed:29053970). Probably acts as an amino acid
CC sensor of the Rag GTPases and Ragulator complexes, 2 complexes involved
CC in amino acid sensing and activation of mTORC1, a signaling complex
CC promoting cell growth in response to growth factors, energy levels, and
CC amino acids (PubMed:25567906, PubMed:29053970). Following activation by
CC amino acids, the Ragulator and Rag GTPases function as a scaffold
CC recruiting mTORC1 to lysosomes where it is in turn activated
CC (PubMed:25561175, PubMed:25567906). SLC38A9 mediates transport of amino
CC acids with low capacity and specificity with a slight preference for
CC polar amino acids (PubMed:25561175, PubMed:25567906). Acts as an
CC arginine sensor (PubMed:25567906, PubMed:29053970, PubMed:31295473).
CC Following activation by arginine binding, mediates transport of L-
CC glutamine, leucine and tyrosine with high efficiency, and is required
CC for the efficient utilization of these amino acids after lysosomal
CC protein degradation (PubMed:29053970, PubMed:31295473). However, the
CC transport mechanism is not well defined and the role of sodium is not
CC clear (PubMed:25561175, PubMed:31295473). Can disassemble the lysosomal
CC folliculin complex (LFC), and thereby triggers GAP activity of
CC FLCN:FNIP2 toward RRAGC (PubMed:32868926). Acts as an cholesterol
CC sensor that conveys increases in lysosomal cholesterol, leading to
CC lysosomal recruitment and activation of mTORC1 via the Rag GTPases
CC (PubMed:28336668). Guanine exchange factor (GEF) that, upon arginine
CC binding, stimulates GDP release from RRAGA and therefore activates the
CC Rag GTPase heterodimer and the mTORC1 pathway in response to nutrient
CC sufficiency (PubMed:30181260). {ECO:0000269|PubMed:25561175,
CC ECO:0000269|PubMed:25567906, ECO:0000269|PubMed:28336668,
CC ECO:0000269|PubMed:29053970, ECO:0000269|PubMed:30181260,
CC ECO:0000269|PubMed:31295473, ECO:0000269|PubMed:32868926,
CC ECO:0000305|PubMed:31295473}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-leucine(in) = L-leucine(out); Xref=Rhea:RHEA:73011,
CC ChEBI:CHEBI:57427; Evidence={ECO:0000269|PubMed:29053970};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-tyrosine(in) = L-tyrosine(out); Xref=Rhea:RHEA:68572,
CC ChEBI:CHEBI:58315; Evidence={ECO:0000269|PubMed:29053970};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-glutamine(out) = L-glutamine(in); Xref=Rhea:RHEA:73419,
CC ChEBI:CHEBI:58359; Evidence={ECO:0000269|PubMed:25561175,
CC ECO:0000269|PubMed:31295473};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-asparagine(out) = L-asparagine(in); Xref=Rhea:RHEA:73423,
CC ChEBI:CHEBI:58048; Evidence={ECO:0000269|PubMed:25561175};
CC -!- ACTIVITY REGULATION: Amino acid transport activity is increased by
CC sodium and is most active at acidic pH (PubMed:25561175,
CC PubMed:31295473). Transport of L-glutamine, leucine and tyrosine is
CC increased by arginine binding (PubMed:29053970, PubMed:31295473).
CC {ECO:0000269|PubMed:25561175, ECO:0000269|PubMed:29053970,
CC ECO:0000269|PubMed:31295473}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=39 mM for L-arginine {ECO:0000269|PubMed:25567906};
CC KM=4 mM for L-arginine {ECO:0000269|PubMed:29053970};
CC KM=90 uM for L-leucine {ECO:0000269|PubMed:29053970};
CC KM=2.7 mM for L-arginine {ECO:0000269|PubMed:31295473};
CC Vmax=8.8 nmol/min/mg enzyme toward L-glutamine
CC {ECO:0000269|PubMed:31295473};
CC -!- SUBUNIT: Associated component of the Ragulator complex (composed of
CC LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5) (PubMed:25561175,
CC PubMed:25567906, PubMed:28336668, PubMed:29053970, PubMed:32868926).
CC Associated component of the Rag GTPases heterodimers (composed of
CC RRAGA, RRAGB, RRAGC and RRAGD); this interaction is independent of the
CC Ragulator complex but depends on the nucleotide loading state of the
CC Rag GTPase heterodimer (PubMed:25561175, PubMed:25567906,
CC PubMed:28336668, PubMed:29053970, PubMed:30181260, PubMed:32868926).
CC Interacts with TM4SF5 (PubMed:30956113). Interacts with NPC1; this
CC interaction inhibits cholesterol-mediated mTORC1 activation via its
CC sterol transport activity (PubMed:28336668).
CC {ECO:0000269|PubMed:25561175, ECO:0000269|PubMed:25567906,
CC ECO:0000269|PubMed:28336668, ECO:0000269|PubMed:29053970,
CC ECO:0000269|PubMed:30181260, ECO:0000269|PubMed:30956113,
CC ECO:0000269|PubMed:32868926}.
CC -!- INTERACTION:
CC Q8NBW4; Q6IAA8: LAMTOR1; NbExp=15; IntAct=EBI-9978316, EBI-715385;
CC Q8NBW4; Q9Y2Q5: LAMTOR2; NbExp=5; IntAct=EBI-9978316, EBI-2643704;
CC Q8NBW4; Q9UHA4: LAMTOR3; NbExp=7; IntAct=EBI-9978316, EBI-1038192;
CC Q8NBW4; Q0VGL1: LAMTOR4; NbExp=6; IntAct=EBI-9978316, EBI-5658976;
CC Q8NBW4; O43504: LAMTOR5; NbExp=6; IntAct=EBI-9978316, EBI-713382;
CC Q8NBW4; Q7L523: RRAGA; NbExp=17; IntAct=EBI-9978316, EBI-752376;
CC Q8NBW4; Q5VZM2: RRAGB; NbExp=2; IntAct=EBI-9978316, EBI-993049;
CC Q8NBW4; Q9HB90: RRAGC; NbExp=9; IntAct=EBI-9978316, EBI-752390;
CC Q8NBW4; O14894: TM4SF5; NbExp=4; IntAct=EBI-9978316, EBI-19125949;
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:25561175,
CC ECO:0000269|PubMed:25567906, ECO:0000269|PubMed:29053970,
CC ECO:0000269|PubMed:30956113}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q08BA4}. Late endosome membrane
CC {ECO:0000269|PubMed:25561175}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q08BA4}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1;
CC IsoId=Q8NBW4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8NBW4-2; Sequence=VSP_032815;
CC Name=3;
CC IsoId=Q8NBW4-3; Sequence=VSP_045111, VSP_045112;
CC Name=4;
CC IsoId=Q8NBW4-4; Sequence=VSP_045110;
CC -!- DOMAIN: The cytosolic N-terminus part of the protein mediates
CC interaction with the Ragulator complex (PubMed:25561175,
CC PubMed:25567906). The cytosolic N-terminus part of the protein
CC destabilizes the LFC and thereby triggers GAP activity of FLCN:FNIP2
CC toward RRAGC (PubMed:32868926). The cytosolic N-terminus part of the
CC protein mediates interaction with the Rag GTPase heterodimer in a RRAGA
CC GDP-loaded state dependent and upon arginine binding, leading to the
CC GDP release and SLC38A9 dissociation from the activated Rag GTPase
CC heterodimer (PubMed:25561175, PubMed:25567906, PubMed:30181260). The
CC cytosolic N-terminus part of the protein exists at least in two
CC distinct conformations; The first is when the N-terminus is bound
CC snugly in the arginine binding site (in the absence of arginine, low
CC luminal arginine state) and the second is where the N-terminus is
CC released and the substrate-binding site is occupied by arginine (in the
CC presence of arginine, high luminal arginine state) (By similarity).
CC {ECO:0000250|UniProtKB:Q08BA4, ECO:0000269|PubMed:25561175,
CC ECO:0000269|PubMed:25567906, ECO:0000269|PubMed:30181260,
CC ECO:0000269|PubMed:32868926}.
CC -!- DOMAIN: The CARC and CRAC motifs mediate binding to cholesterol.
CC {ECO:0000269|PubMed:28336668}.
CC -!- PTM: Glycosylated. {ECO:0000269|PubMed:25561175,
CC ECO:0000269|PubMed:25567906}.
CC -!- SIMILARITY: Belongs to the amino acid/polyamine transporter 2 family.
CC SLC38A9 subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAQ19756.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AK075190; BAC11460.1; -; mRNA.
DR EMBL; AK127988; BAG54613.1; -; mRNA.
DR EMBL; AK301850; BAH13566.1; -; mRNA.
DR EMBL; AB105188; BAQ19756.1; ALT_INIT; mRNA.
DR EMBL; AC008784; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC016632; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471123; EAW54926.1; -; Genomic_DNA.
DR EMBL; BC066891; AAH66891.1; -; mRNA.
DR EMBL; BC101362; AAI01363.1; -; mRNA.
DR EMBL; BX641065; CAE46032.1; -; mRNA.
DR CCDS; CCDS3968.1; -. [Q8NBW4-1]
DR CCDS; CCDS58947.1; -. [Q8NBW4-4]
DR CCDS; CCDS58948.1; -. [Q8NBW4-3]
DR RefSeq; NP_001245215.1; NM_001258286.1. [Q8NBW4-4]
DR RefSeq; NP_001245216.1; NM_001258287.1. [Q8NBW4-3]
DR RefSeq; NP_775785.2; NM_173514.3. [Q8NBW4-1]
DR RefSeq; XP_006714600.1; XM_006714537.2.
DR RefSeq; XP_006714601.1; XM_006714538.3.
DR RefSeq; XP_006714602.1; XM_006714539.3. [Q8NBW4-1]
DR RefSeq; XP_011541475.1; XM_011543173.1.
DR RefSeq; XP_011541476.1; XM_011543174.1. [Q8NBW4-1]
DR PDB; 6WJ2; EM; 3.20 A; H=1-119.
DR PDB; 6WJ3; EM; 3.90 A; H=1-119.
DR PDB; 8DHB; EM; 3.53 A; H=1-119.
DR PDBsum; 6WJ2; -.
DR PDBsum; 6WJ3; -.
DR PDBsum; 8DHB; -.
DR AlphaFoldDB; Q8NBW4; -.
DR EMDB; EMD-21686; -.
DR EMDB; EMD-21687; -.
DR EMDB; EMD-27435; -.
DR SMR; Q8NBW4; -.
DR BioGRID; 127480; 35.
DR DIP; DIP-61480N; -.
DR IntAct; Q8NBW4; 30.
DR STRING; 9606.ENSP00000380074; -.
DR TCDB; 2.A.18.9.1; the amino acid/auxin permease (aaap) family.
DR GlyCosmos; Q8NBW4; 4 sites, No reported glycans.
DR GlyGen; Q8NBW4; 4 sites.
DR iPTMnet; Q8NBW4; -.
DR PhosphoSitePlus; Q8NBW4; -.
DR BioMuta; SLC38A9; -.
DR DMDM; 296452888; -.
DR jPOST; Q8NBW4; -.
DR MassIVE; Q8NBW4; -.
DR PaxDb; 9606-ENSP00000380074; -.
DR PeptideAtlas; Q8NBW4; -.
DR ProteomicsDB; 3820; -.
DR ProteomicsDB; 6851; -.
DR ProteomicsDB; 72830; -. [Q8NBW4-1]
DR ProteomicsDB; 72831; -. [Q8NBW4-2]
DR Pumba; Q8NBW4; -.
DR Antibodypedia; 23436; 85 antibodies from 16 providers.
DR DNASU; 153129; -.
DR Ensembl; ENST00000318672.7; ENSP00000316596.3; ENSG00000177058.12. [Q8NBW4-1]
DR Ensembl; ENST00000396865.7; ENSP00000380074.2; ENSG00000177058.12. [Q8NBW4-1]
DR Ensembl; ENST00000512595.5; ENSP00000427335.1; ENSG00000177058.12. [Q8NBW4-3]
DR Ensembl; ENST00000515629.5; ENSP00000420934.1; ENSG00000177058.12. [Q8NBW4-4]
DR GeneID; 153129; -.
DR KEGG; hsa:153129; -.
DR MANE-Select; ENST00000396865.7; ENSP00000380074.2; NM_173514.4; NP_775785.2.
DR UCSC; uc003jqd.4; human. [Q8NBW4-1]
DR AGR; HGNC:26907; -.
DR CTD; 153129; -.
DR DisGeNET; 153129; -.
DR GeneCards; SLC38A9; -.
DR HGNC; HGNC:26907; SLC38A9.
DR HPA; ENSG00000177058; Tissue enhanced (placenta).
DR MIM; 616203; gene.
DR neXtProt; NX_Q8NBW4; -.
DR OpenTargets; ENSG00000177058; -.
DR PharmGKB; PA162403774; -.
DR VEuPathDB; HostDB:ENSG00000177058; -.
DR eggNOG; KOG1305; Eukaryota.
DR GeneTree; ENSGT00390000005646; -.
DR InParanoid; Q8NBW4; -.
DR OMA; HWFTPTE; -.
DR OrthoDB; 294730at2759; -.
DR PhylomeDB; Q8NBW4; -.
DR TreeFam; TF312989; -.
DR PathwayCommons; Q8NBW4; -.
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; Q8NBW4; -.
DR SIGNOR; Q8NBW4; -.
DR BioGRID-ORCS; 153129; 6 hits in 1153 CRISPR screens.
DR ChiTaRS; SLC38A9; human.
DR GenomeRNAi; 153129; -.
DR Pharos; Q8NBW4; Tbio.
DR PRO; PR:Q8NBW4; -.
DR Proteomes; UP000005640; Chromosome 5.
DR RNAct; Q8NBW4; protein.
DR Bgee; ENSG00000177058; Expressed in secondary oocyte and 173 other cell types or tissues.
DR ExpressionAtlas; Q8NBW4; baseline and differential.
DR GO; GO:1990877; C:FNIP-folliculin RagC/D GAP; IDA:UniProtKB.
DR GO; GO:0005770; C:late endosome; IDA:UniProtKB.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0015171; F:amino acid transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0034618; F:arginine binding; ISS:UniProtKB.
DR GO; GO:0015485; F:cholesterol binding; IDA:UniProtKB.
DR GO; GO:0005085; F:guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0015179; F:L-amino acid transmembrane transporter activity; IBA:GO_Central.
DR GO; GO:0061459; F:L-arginine transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015182; F:L-asparagine transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015186; F:L-glutamine transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0015190; F:L-leucine transmembrane transporter activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0032935; F:sterol sensor activity; IDA:UniProtKB.
DR GO; GO:0003333; P:amino acid transmembrane transport; IDA:UniProtKB.
DR GO; GO:0006867; P:asparagine transport; IDA:UniProtKB.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IDA:UniProtKB.
DR GO; GO:0006868; P:glutamine transport; IDA:UniProtKB.
DR GO; GO:1903826; P:L-arginine transmembrane transport; IDA:UniProtKB.
DR GO; GO:0032008; P:positive regulation of TOR signaling; IDA:UniProtKB.
DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IDA:UniProtKB.
DR InterPro; IPR013057; AA_transpt_TM.
DR PANTHER; PTHR22950; AMINO ACID TRANSPORTER; 1.
DR PANTHER; PTHR22950:SF244; NEUTRAL AMINO ACID TRANSPORTER 9; 1.
DR Pfam; PF01490; Aa_trans; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amino-acid transport; Disulfide bond;
KW Endosome; Glycoprotein; Lysosome; Membrane; Metal-binding;
KW Proteomics identification; Reference proteome; Sodium; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..561
FT /note="Neutral amino acid transporter 9"
FT /id="PRO_0000328840"
FT TOPO_DOM 1..119
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305|PubMed:25561175"
FT TRANSMEM 120..140
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 141..146
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 147..167
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 168..198
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 199..225
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 226..283
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 284..300
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 301..309
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 310..334
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 335..356
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 357..377
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 378..394
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 395..415
FT /note="Helical; Name=7"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 416..437
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 438..458
FT /note="Helical; Name=8"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 459..479
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 480..500
FT /note="Helical; Name=9"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 501..507
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 508..528
FT /note="Helical; Name=10"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT TOPO_DOM 529..540
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 541..561
FT /note="Helical; Name=11"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT REGION 1..30
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 129..134
FT /note="Important for arginine binding and amino acid
FT transport"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT MOTIF 444..454
FT /note="CARC motif"
FT /evidence="ECO:0000269|PubMed:28336668"
FT MOTIF 457..463
FT /note="CRAC motif"
FT /evidence="ECO:0000269|PubMed:28336668"
FT COMPBIAS 7..22
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 134
FT /ligand="arginine"
FT /ligand_id="ChEBI:CHEBI:32696"
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT CARBOHYD 239
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 248
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 266
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 274
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 255..424
FT /evidence="ECO:0000250|UniProtKB:Q08BA4"
FT VAR_SEQ 1..63
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045110"
FT VAR_SEQ 1..37
FT /note="MANMNSDSRHLGTSEVDHERDPGPMNIQFEPSDLRSK -> MAICILTWRI
FT (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045111"
FT VAR_SEQ 318..353
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045112"
FT VAR_SEQ 428..561
FT /note="NFLDNFPSSDTLSFIARIFLLFQMMTVYPLLGYLARVQLLGHIFGDIYPSIF
FT HVLILNLIIVGAGVIMACFYPNIGGIIRYSGAACGLAFVFIYPSLIYIISLHQEERLTW
FT PKLIFHVFIIILGVANLIVQFFM -> VRHRVPSLCDCVHFHVFIVGRVIQWQDITSDR
FT PGF (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:17974005"
FT /id="VSP_032815"
FT VARIANT 182
FT /note="S -> T (in dbSNP:rs4865615)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005"
FT /id="VAR_042546"
FT MUTAGEN 38..40
FT /note="RPF->AAA: Abolishes interaction with the Ragulator
FT and Rag GTPases complexes."
FT /evidence="ECO:0000269|PubMed:25561175"
FT MUTAGEN 60
FT /note="H->A: Does not affect association with the Ragulator
FT complex. Abolishes the interaction with the Rag GTPases
FT heterodimer complex."
FT /evidence="ECO:0000269|PubMed:25567906,
FT ECO:0000269|PubMed:32868926"
FT MUTAGEN 68
FT /note="I->A: Abolishes association with the Ragulator
FT complex. No effect on amino acid transport activity.
FT Abolishes the interaction with the Rag GTPases heterodimer
FT complex."
FT /evidence="ECO:0000269|PubMed:25567906,
FT ECO:0000269|PubMed:29053970, ECO:0000269|PubMed:32868926"
FT MUTAGEN 70..73
FT /note="YYSR->AAAA: Abolishes interaction with the Ragulator
FT and Rag GTPases complexes."
FT /evidence="ECO:0000269|PubMed:25561175"
FT MUTAGEN 71
FT /note="Y->A: Abolishes association with the Ragulator
FT complex. Abolishes the interaction with the Rag GTPases
FT heterodimer complex."
FT /evidence="ECO:0000269|PubMed:25567906,
FT ECO:0000269|PubMed:32868926"
FT MUTAGEN 74
FT /note="L->A: Abolishes association with the Ragulator
FT complex. Abolishes the interaction with the Rag GTPases
FT heterodimer complex."
FT /evidence="ECO:0000269|PubMed:25567906,
FT ECO:0000269|PubMed:32868926"
FT MUTAGEN 85..87
FT /note="PDH->AAA: Abolishes interaction with the Ragulator
FT and Rag GTPases complexes."
FT /evidence="ECO:0000269|PubMed:25561175"
FT MUTAGEN 85
FT /note="P->A: Abolishes association with the Ragulator
FT complex."
FT /evidence="ECO:0000269|PubMed:25567906"
FT MUTAGEN 90
FT /note="P->A: Abolishes association with the Ragulator
FT complex."
FT /evidence="ECO:0000269|PubMed:25567906"
FT MUTAGEN 98..101
FT /note="YSPL->AAAA: Does not affect interaction with the
FT Ragulator and Rag GTPases complexes."
FT /evidence="ECO:0000269|PubMed:25561175"
FT MUTAGEN 128
FT /note="N->A: Moderately affects amino acid transport."
FT /evidence="ECO:0000269|PubMed:25561175"
FT MUTAGEN 133
FT /note="T->W: Abolishes arginine transport. No effect on
FT subcellular location and interaction with Ragulator
FT complex."
FT /evidence="ECO:0000269|PubMed:29053970"
FT MUTAGEN 449
FT /note="F->I: Abolishes cholesterol binding; when associated
FT with I-460. Does not affect disrupted arginine-mediated
FT activation of mTORC1; when associated with I-460. Does not
FT affect lysosomal localization; when associated with I-460.
FT Increases interactions with both Rag GTPase and Ragulator
FT subunits; when associated with I-460. Loss of L-glutamine
FT transport stimulation by cholesterol."
FT /evidence="ECO:0000269|PubMed:28336668,
FT ECO:0000269|PubMed:31295473"
FT MUTAGEN 453
FT /note="T->A: Does not affect L-glutamine transport
FT activity."
FT /evidence="ECO:0000269|PubMed:31295473"
FT MUTAGEN 460
FT /note="Y->I: Decreases cholesterol binding. Abolishes
FT cholesterol binding; when associated with I-449. Does not
FT affect disrupted arginine-mediated activation of mTORC1;
FT when associated with I-449. Does not affect lysosomal
FT localization; when associated with I-449. Increases
FT interactions with both Rag GTPase and Ragulator subunits;
FT when associated with I-449. Loss of L-glutamine transport
FT stimulation by cholesterol."
FT /evidence="ECO:0000269|PubMed:28336668,
FT ECO:0000269|PubMed:31295473"
FT CONFLICT 84
FT /note="A -> P (in Ref. 5; AAH66891)"
FT /evidence="ECO:0000305"
FT STRAND 48..50
FT /evidence="ECO:0007829|PDB:6WJ2"
FT HELIX 61..72
FT /evidence="ECO:0007829|PDB:6WJ2"
FT TURN 86..88
FT /evidence="ECO:0007829|PDB:6WJ2"
FT TURN 93..95
FT /evidence="ECO:0007829|PDB:6WJ2"
SQ SEQUENCE 561 AA; 63776 MW; 0C1A3A136158168A CRC64;
MANMNSDSRH LGTSEVDHER DPGPMNIQFE PSDLRSKRPF CIEPTNIVNV NHVIQRVSDH
ASAMNKRIHY YSRLTTPADK ALIAPDHVVP APEECYVYSP LGSAYKLQSY TEGYGKNTSL
VTIFMIWNTM MGTSILSIPW GIKQAGFTTG MCVIILMGLL TLYCCYRVVK SRTMMFSLDT
TSWEYPDVCR HYFGSFGQWS SLLFSLVSLI GAMIVYWVLM SNFLFNTGKF IFNFIHHIND
TDTILSTNNS NPVICPSAGS GGHPDNSSMI FYANDTGAQQ FEKWWDKSRT VPFYLVGLLL
PLLNFKSPSF FSKFNILGTV SVLYLIFLVT FKAVRLGFHL EFHWFIPTEF FVPEIRFQFP
QLTGVLTLAF FIHNCIITLL KNNKKQENNV RDLCIAYMLV TLTYLYIGVL VFASFPSPPL
SKDCIEQNFL DNFPSSDTLS FIARIFLLFQ MMTVYPLLGY LARVQLLGHI FGDIYPSIFH
VLILNLIIVG AGVIMACFYP NIGGIIRYSG AACGLAFVFI YPSLIYIISL HQEERLTWPK
LIFHVFIIIL GVANLIVQFF M
//