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 24-JAN-2024, entry version 157. 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:25567906, CC PubMed:25561175, 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:25567906, PubMed:25561175). 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:32868926, PubMed:28336668, PubMed:25567906, PubMed:29053970). 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:32868926, CC PubMed:28336668, PubMed:30181260, PubMed:25567906, PubMed:29053970). 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=12; IntAct=EBI-9978316, EBI-715385; CC Q8NBW4; Q9Y2Q5: LAMTOR2; NbExp=3; IntAct=EBI-9978316, EBI-2643704; CC Q8NBW4; Q9UHA4: LAMTOR3; NbExp=5; IntAct=EBI-9978316, EBI-1038192; CC Q8NBW4; Q0VGL1: LAMTOR4; NbExp=4; IntAct=EBI-9978316, EBI-5658976; CC Q8NBW4; O43504: LAMTOR5; NbExp=4; IntAct=EBI-9978316, EBI-713382; CC Q8NBW4; Q7L523: RRAGA; NbExp=16; 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 -!- 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:30181260, PubMed:25561175, PubMed:25567906). 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}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 34. DR DIP; DIP-61480N; -. DR IntAct; Q8NBW4; 26. 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 EPD; Q8NBW4; -. DR jPOST; Q8NBW4; -. DR MassIVE; Q8NBW4; -. DR MaxQB; 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; 71 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; 51748at2759; -. 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; SODIUM-COUPLED NEUTRAL AMINO ACID TRANSPORTER 9; 1. DR Pfam; PF01490; Aa_trans; 2. DR Genevisible; Q8NBW4; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Amino-acid transport; Disulfide bond; KW Endosome; Glycoprotein; Lysosome; Membrane; Metal-binding; KW Reference proteome; Sodium; Transmembrane; 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 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 //