NPC2_HUMAN
ID NPC2_HUMAN Reviewed; 151 AA.
AC P61916; B4DQV7; Q15668; Q29413;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
DT 07-JUN-2004, sequence version 1.
DT 03-AUG-2022, entry version 166.
DE RecName: Full=NPC intracellular cholesterol transporter 2 {ECO:0000312|HGNC:HGNC:14537};
DE AltName: Full=Epididymal secretory protein E1;
DE AltName: Full=Human epididymis-specific protein 1;
DE Short=He1 {ECO:0000303|PubMed:11125141, ECO:0000303|PubMed:8418812};
DE AltName: Full=Niemann-Pick disease type C2 protein {ECO:0000303|PubMed:17018531};
DE Flags: Precursor;
GN Name=NPC2 {ECO:0000312|HGNC:HGNC:14537}; Synonyms=HE1;
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] (ISOFORM 1).
RC TISSUE=Epididymis;
RX PubMed=8418812; DOI=10.1002/mrd.1080340104;
RA Krull N., Ivell R., Osterhoff C., Kirchhoff C.;
RT "Region-specific variation of gene expression in the human epididymis as
RT revealed by in situ hybridization with tissue-specific cDNAs.";
RL Mol. Reprod. Dev. 34:16-24(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Ovary;
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 [5]
RP PROTEIN SEQUENCE OF N-TERMINUS, GLYCOSYLATION AT ASN-58 AND ASN-135, AND
RP FUNCTION.
RC TISSUE=Brain;
RX PubMed=17018531; DOI=10.1074/jbc.m608743200;
RA Liou H.L., Dixit S.S., Xu S., Tint G.S., Stock A.M., Lobel P.;
RT "NPC2, the protein deficient in Niemann-Pick C2 disease, consists of
RT multiple glycoforms that bind a variety of sterols.";
RL J. Biol. Chem. 281:36710-36723(2006).
RN [6]
RP INVOLVEMENT IN NPC2, PROTEIN SEQUENCE OF N-TERMINUS, TISSUE SPECIFICITY,
RP AND SUBCELLULAR LOCATION.
RX PubMed=11125141; DOI=10.1126/science.290.5500.2298;
RA Naureckiene S., Sleat D.E., Lackland H., Fensom A., Vanier M.T.,
RA Wattiaux R., Jadot M., Lobel P.;
RT "Identification of HE1 as the second gene of Niemann-Pick C disease.";
RL Science 290:2298-2301(2000).
RN [7]
RP INTERACTION WITH DHDDS.
RX PubMed=15110773; DOI=10.1016/j.bbrc.2004.04.007;
RA Kharel Y., Takahashi S., Yamashita S., Koyama T.;
RT "In vivo interaction between the human dehydrodolichyl diphosphate synthase
RT and the Niemann-Pick C2 protein revealed by a yeast two-hybrid system.";
RL Biochem. Biophys. Res. Commun. 318:198-203(2004).
RN [8]
RP INDUCTION, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells reveal
RT differential cellular gene expression in response to enterovirus 71
RT infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [9]
RP FUNCTION.
RX PubMed=18823126; DOI=10.1021/bi801328u;
RA Xu Z., Farver W., Kodukula S., Storch J.;
RT "Regulation of sterol transport between membranes and NPC2.";
RL Biochemistry 47:11134-11143(2008).
RN [10]
RP FUNCTION, INTERACTION WITH NPC1, CHARACTERIZATION OF VARIANT NPC2 SER-120,
RP AND CATALYTIC ACTIVITY.
RX PubMed=18772377; DOI=10.1073/pnas.0807328105;
RA Infante R.E., Wang M.L., Radhakrishnan A., Kwon H.J., Brown M.S.,
RA Goldstein J.L.;
RT "NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and
RT lipid bilayers, a step in cholesterol egress from lysosomes.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:15287-15292(2008).
RN [11]
RP INTERACTION WITH NEDD4L, AND TISSUE SPECIFICITY.
RX PubMed=19664597; DOI=10.1016/j.bbrc.2009.07.158;
RA Araki N., Ishigami T., Ushio H., Minegishi S., Umemura M., Miyagi Y.,
RA Aoki I., Morinaga H., Tamura K., Toya Y., Uchino K., Umemura S.;
RT "Identification of NPC2 protein as interaction molecule with C2 domain of
RT human Nedd4L.";
RL Biochem. Biophys. Res. Commun. 388:290-296(2009).
RN [12]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH NUS1.
RX PubMed=19723497; DOI=10.1016/j.cmet.2009.07.003;
RA Harrison K.D., Miao R.Q., Fernandez-Hernando C., Suarez Y., Davalos A.,
RA Sessa W.C.;
RT "Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates
RT intracellular cholesterol trafficking.";
RL Cell Metab. 10:208-218(2009).
RN [13]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-135.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of multiple
RT enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [14]
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 [15]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=21315718; DOI=10.1053/j.gastro.2011.01.050;
RA Yamanashi Y., Takada T., Yoshikado T., Shoda J., Suzuki H.;
RT "NPC2 regulates biliary cholesterol secretion via stimulation of ABCG5/G8-
RT mediated cholesterol transport.";
RL Gastroenterology 140:1664-1674(2011).
RN [16]
RP INTERACTION WITH NPC1L1.
RX PubMed=22095670; DOI=10.1002/hep.24772;
RA Yamanashi Y., Takada T., Shoda J., Suzuki H.;
RT "Novel function of Niemann-Pick C1-like 1 as a negative regulator of
RT Niemann-Pick C2 protein.";
RL Hepatology 55:953-964(2012).
RN [17]
RP REVIEW ON FUNCTION.
RX PubMed=18832164; DOI=10.1073/pnas.0808256105;
RA Subramanian K., Balch W.E.;
RT "NPC1/NPC2 function as a tag team duo to mobilize cholesterol.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:15223-15224(2008).
RN [18]
RP REVIEW ON FUNCTION.
RX PubMed=19232397; DOI=10.1016/j.bbalip.2009.02.001;
RA Storch J., Xu Z.;
RT "Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking.";
RL Biochim. Biophys. Acta 1791:671-678(2009).
RN [19]
RP REVIEW ON FUNCTION.
RX PubMed=20674853; DOI=10.1016/j.cmet.2010.07.004;
RA Vance J.E.;
RT "Transfer of cholesterol by the NPC team.";
RL Cell Metab. 12:105-106(2010).
RN [20]
RP REVIEW ON FUNCTION.
RX PubMed=21412152; DOI=10.1097/mol.0b013e3283453e69;
RA Vance J.E., Peake K.B.;
RT "Function of the Niemann-Pick type C proteins and their bypass by
RT cyclodextrin.";
RL Curr. Opin. Lipidol. 22:204-209(2011).
RN [21]
RP IDENTIFICATION BY 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 [22]
RP IDENTIFICATION BY MASS SPECTROMETRY [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 [23]
RP FUNCTION, AND INTERACTION WITH NPC1.
RX PubMed=27238017; DOI=10.1016/j.cell.2016.05.022;
RA Gong X., Qian H., Zhou X., Wu J., Wan T., Cao P., Huang W., Zhao X.,
RA Wang X., Wang P., Shi Y., Gao G.F., Zhou Q., Yan N.;
RT "Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol
RT Transfer and Ebola Infection.";
RL Cell 165:1467-1478(2016).
RN [24]
RP FUNCTION.
RX PubMed=29580834; DOI=10.1016/j.chemphyslip.2018.03.006;
RA Berzina Z., Solanko L.M., Mehadi A.S., Jensen M.L.V., Lund F.W., Modzel M.,
RA Szomek M., Solanko K.A., Dupont A., Nielsen G.K., Heegaard C.W.,
RA Ejsing C.S., Wuestner D.;
RT "Niemann-Pick C2 protein regulates sterol transport between plasma membrane
RT and late endosomes in human fibroblasts.";
RL Chem. Phys. Lipids 213:48-61(2018).
RN [25] {ECO:0007744|PDB:5KWY}
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 20-151 IN COMPLEX WITH
RP CHOLESTEROL AND NPC1, INTERACTION WITH NPC1, GLYCOSYLATION AT ASN-58 AND
RP ASN-135, AND DISULFIDE BONDS.
RX PubMed=27551080; DOI=10.1073/pnas.1611956113;
RA Li X., Saha P., Li J., Blobel G., Pfeffer S.R.;
RT "Clues to the mechanism of cholesterol transfer from the structure of NPC1
RT middle lumenal domain bound to NPC2.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:10079-10084(2016).
RN [26]
RP VARIANT NPC2 PRO-67.
RX PubMed=11567215; DOI=10.1086/324068;
RA Millat G., Chikh K., Naureckiene S., Sleat D.E., Fensom A.H., Higaki K.,
RA Elleder M., Lobel P., Vanier M.T.;
RT "Niemann-Pick disease type C: spectrum of HE1 mutations and
RT genotype/phenotype correlations in the NPC2 group.";
RL Am. J. Hum. Genet. 69:1013-1021(2001).
RN [27]
RP VARIANT NPC2 MET-39.
RX PubMed=12447927; DOI=10.1002/ana.10366;
RA Klunemann H.H., Elleder M., Kaminski W.E., Snow K., Peyser J.M.,
RA O'Brien J.F., Munoz D., Schmitz G., Klein H.E., Pendlebury W.W.;
RT "Frontal lobe atrophy due to a mutation in the cholesterol binding protein
RT HE1/NPC2.";
RL Ann. Neurol. 52:743-749(2002).
RN [28]
RP VARIANTS NPC2 MET-30; PHE-47 AND PHE-93.
RX PubMed=12955717; DOI=10.1002/humu.10255;
RA Park W.D., O'Brien J.F., Lundquist P.A., Kraft D.L., Vockley C.W.,
RA Karnes P.S., Patterson M.C., Snow K.;
RT "Identification of 58 novel mutations in Niemann-Pick disease type C:
RT correlation with biochemical phenotype and importance of PTC1-like domains
RT in NPC1.";
RL Hum. Mutat. 22:313-325(2003).
RN [29]
RP VARIANT NPC2 ARG-99, CHARACTERIZATION OF VARIANTS NPC2 METH-39; PHE-47;
RP PRO-67; PHE-93 AND ARG-99, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=15937921; DOI=10.1002/humu.20173;
RA Chikh K., Rodriguez C., Vey S., Vanier M.T., Millat G.;
RT "Niemann-Pick type C disease: subcellular location and functional
RT characterization of NPC2 proteins with naturally occurring missense
RT mutations.";
RL Hum. Mutat. 26:20-28(2005).
RN [30]
RP VARIANT NPC2 SER-120.
RX PubMed=16126423; DOI=10.1016/j.ymgme.2005.07.007;
RA Millat G., Baielo N., Molinero S., Rodriguez C., Chikh K., Vanier M.T.;
RT "Niemann-Pick C disease: use of denaturing high performance liquid
RT chromatography for the detection of NPC1 and NPC2 genetic variations and
RT impact on management of patients and families.";
RL Mol. Genet. Metab. 86:220-232(2005).
CC -!- FUNCTION: Intracellular cholesterol transporter which acts in concert
CC with NPC1 and plays an important role in the egress of cholesterol from
CC the lysosomal compartment (PubMed:17018531, PubMed:11125141,
CC PubMed:18772377, PubMed:29580834, PubMed:15937921). Unesterified
CC cholesterol that has been released from LDLs in the lumen of the late
CC endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding
CC pocket in the N-terminal domain of NPC1 (PubMed:17018531,
CC PubMed:18772377, PubMed:27238017). May bind and mobilize cholesterol
CC that is associated with membranes (PubMed:18823126). NPC2 binds
CC cholesterol with a 1:1 stoichiometry (PubMed:17018531). Can bind a
CC variety of sterols, including lathosterol, desmosterol and the plant
CC sterols stigmasterol and beta-sitosterol (PubMed:17018531). The
CC secreted form of NCP2 regulates biliary cholesterol secretion via
CC stimulation of ABCG5/ABCG8-mediated cholesterol transport (By
CC similarity). {ECO:0000250|UniProtKB:Q9Z0J0,
CC ECO:0000269|PubMed:11125141, ECO:0000269|PubMed:15937921,
CC ECO:0000269|PubMed:17018531, ECO:0000269|PubMed:18772377,
CC ECO:0000269|PubMed:18823126, ECO:0000269|PubMed:27238017,
CC ECO:0000269|PubMed:29580834}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol(in) = cholesterol(out); Xref=Rhea:RHEA:39747,
CC ChEBI:CHEBI:16113; Evidence={ECO:0000269|PubMed:18772377};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:39748;
CC Evidence={ECO:0000269|PubMed:18772377};
CC -!- SUBUNIT: Interacts with NPC1 (via the second lumenal domain) in a
CC cholestrol-dependent manner (PubMed:18772377, PubMed:27238017,
CC PubMed:27551080). Interacts with NUS1/NgBR, the interaction stabilizes
CC NCP2 and regulates cholesterol trafficking (PubMed:19723497). Interacts
CC with DHDDS (PubMed:15110773). Interacts with NEDD4L (via C2 domain)
CC (PubMed:19664597). Interacts with NPC1L1 (PubMed:22095670).
CC {ECO:0000269|PubMed:15110773, ECO:0000269|PubMed:18772377,
CC ECO:0000269|PubMed:19664597, ECO:0000269|PubMed:19723497,
CC ECO:0000269|PubMed:22095670, ECO:0000269|PubMed:27238017,
CC ECO:0000269|PubMed:27551080}.
CC -!- INTERACTION:
CC P61916; Q7Z3B1: NEGR1; NbExp=9; IntAct=EBI-2368946, EBI-4314838;
CC P61916; O15118: NPC1; NbExp=3; IntAct=EBI-2368946, EBI-2368710;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11125141,
CC ECO:0000269|PubMed:15937921, ECO:0000269|PubMed:19723497,
CC ECO:0000269|PubMed:21315718}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:19723497}. Lysosome {ECO:0000269|PubMed:15937921,
CC ECO:0000269|PubMed:19723497, ECO:0000305|PubMed:11125141}.
CC Note=Interaction with cell-surface M6PR mediates endocytosis and
CC targeting to lysosomes. {ECO:0000305|PubMed:11125141}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P61916-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P61916-2; Sequence=VSP_056459;
CC -!- TISSUE SPECIFICITY: Detected in gallbladder bile (PubMed:21315718).
CC Detected in fibroblasts, kidney, liver, spleen, small intestine,
CC placenta and testis (at protein level) (PubMed:11125141). Epididymis.
CC {ECO:0000269|PubMed:11125141, ECO:0000269|PubMed:19664597,
CC ECO:0000269|PubMed:21315718}.
CC -!- INDUCTION: Down-regulated in response to enterovirus 71 (EV71)
CC infection. {ECO:0000269|PubMed:16548883}.
CC -!- DOMAIN: Binds cholesterol in a hydrophobic pocket; there are no
CC hydrogen bonds between the sterol and the protein.
CC {ECO:0000250|UniProtKB:P79345}.
CC -!- DISEASE: Niemann-Pick disease C2 (NPC2) [MIM:607625]: A lysosomal
CC storage disorder that affects the viscera and the central nervous
CC system. It is due to defective intracellular processing and transport
CC of low-density lipoprotein derived cholesterol. It causes accumulation
CC of cholesterol in lysosomes, with delayed induction of cholesterol
CC homeostatic reactions. Niemann-Pick disease type C2 has a highly
CC variable clinical phenotype. Clinical features include variable
CC hepatosplenomegaly and severe progressive neurological dysfunction such
CC as ataxia, dystonia and dementia. The age of onset can vary from
CC infancy to late adulthood. {ECO:0000269|PubMed:11125141,
CC ECO:0000269|PubMed:11567215, ECO:0000269|PubMed:12447927,
CC ECO:0000269|PubMed:12955717, ECO:0000269|PubMed:15937921,
CC ECO:0000269|PubMed:16126423, ECO:0000269|PubMed:18772377}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the NPC2 family. {ECO:0000305}.
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DR EMBL; X67698; CAA47928.1; -; mRNA.
DR EMBL; AK298975; BAG61069.1; -; mRNA.
DR EMBL; AC005479; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC002532; AAH02532.1; -; mRNA.
DR CCDS; CCDS32121.1; -. [P61916-1]
DR PIR; I38365; I38365.
DR RefSeq; NP_006423.1; NM_006432.3. [P61916-1]
DR PDB; 5KWY; X-ray; 2.40 A; C/D=20-151.
DR PDB; 6W5V; EM; 4.00 A; D=1-151.
DR PDBsum; 5KWY; -.
DR PDBsum; 6W5V; -.
DR AlphaFoldDB; P61916; -.
DR SMR; P61916; -.
DR BioGRID; 115828; 54.
DR IntAct; P61916; 19.
DR MINT; P61916; -.
DR STRING; 9606.ENSP00000451112; -.
DR SwissLipids; SLP:000000475; -.
DR TCDB; 2.A.6.6.1; the resistance-nodulation-cell division (rnd) superfamily.
DR GlyConnect; 1215; 2 N-Linked glycans (1 site).
DR GlyGen; P61916; 2 sites, 2 N-linked glycans (1 site).
DR iPTMnet; P61916; -.
DR MetOSite; P61916; -.
DR PhosphoSitePlus; P61916; -.
DR BioMuta; NPC2; -.
DR DMDM; 48429027; -.
DR EPD; P61916; -.
DR jPOST; P61916; -.
DR MassIVE; P61916; -.
DR MaxQB; P61916; -.
DR PaxDb; P61916; -.
DR PeptideAtlas; P61916; -.
DR PRIDE; P61916; -.
DR ProteomicsDB; 4905; -.
DR ProteomicsDB; 57337; -. [P61916-1]
DR TopDownProteomics; P61916-2; -. [P61916-2]
DR Antibodypedia; 88; 320 antibodies from 34 providers.
DR DNASU; 10577; -.
DR Ensembl; ENST00000541064.5; ENSP00000442488.1; ENSG00000119655.11. [P61916-2]
DR Ensembl; ENST00000555619.6; ENSP00000451112.2; ENSG00000119655.11. [P61916-1]
DR GeneID; 10577; -.
DR KEGG; hsa:10577; -.
DR MANE-Select; ENST00000555619.6; ENSP00000451112.2; NM_006432.5; NP_006423.1.
DR UCSC; uc001xpy.4; human. [P61916-1]
DR CTD; 10577; -.
DR DisGeNET; 10577; -.
DR GeneCards; NPC2; -.
DR GeneReviews; NPC2; -.
DR HGNC; HGNC:14537; NPC2.
DR HPA; ENSG00000119655; Tissue enriched (epididymis).
DR MalaCards; NPC2; -.
DR MIM; 601015; gene.
DR MIM; 607625; phenotype.
DR neXtProt; NX_P61916; -.
DR OpenTargets; ENSG00000119655; -.
DR Orphanet; 216986; Niemann-Pick disease type C, adult neurologic onset.
DR Orphanet; 216981; Niemann-Pick disease type C, juvenile neurologic onset.
DR Orphanet; 216978; Niemann-Pick disease type C, late infantile neurologic onset.
DR Orphanet; 216975; Niemann-Pick disease type C, severe early infantile neurologic onset.
DR Orphanet; 216972; Niemann-Pick disease type C, severe perinatal form.
DR PharmGKB; PA31700; -.
DR VEuPathDB; HostDB:ENSG00000119655; -.
DR eggNOG; KOG4063; Eukaryota.
DR GeneTree; ENSGT00390000006223; -.
DR InParanoid; P61916; -.
DR PhylomeDB; P61916; -.
DR TreeFam; TF317963; -.
DR PathwayCommons; P61916; -.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR Reactome; R-HSA-8964038; LDL clearance.
DR SignaLink; P61916; -.
DR SIGNOR; P61916; -.
DR BioGRID-ORCS; 10577; 21 hits in 1092 CRISPR screens.
DR ChiTaRS; NPC2; human.
DR GenomeRNAi; 10577; -.
DR Pharos; P61916; Tbio.
DR PRO; PR:P61916; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; P61916; protein.
DR Bgee; ENSG00000119655; Expressed in corpus epididymis and 207 other tissues.
DR ExpressionAtlas; P61916; baseline and differential.
DR Genevisible; P61916; HS.
DR GO; GO:0035578; C:azurophil granule lumen; TAS:Reactome.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IMP:UniProtKB.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0015485; F:cholesterol binding; IDA:UniProtKB.
DR GO; GO:0120020; F:cholesterol transfer activity; IDA:BHF-UCL.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0032934; F:sterol binding; IBA:GO_Central.
DR GO; GO:0033344; P:cholesterol efflux; IDA:BHF-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IDA:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0030301; P:cholesterol transport; IDA:UniProtKB.
DR GO; GO:0046836; P:glycolipid transport; TAS:HGNC-UCL.
DR GO; GO:0032367; P:intracellular cholesterol transport; IDA:UniProtKB.
DR GO; GO:0032366; P:intracellular sterol transport; IDA:HGNC-UCL.
DR GO; GO:0015914; P:phospholipid transport; TAS:HGNC-UCL.
DR GO; GO:0019747; P:regulation of isoprenoid metabolic process; TAS:UniProtKB.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR GO; GO:0015918; P:sterol transport; IBA:GO_Central.
DR CDD; cd00916; Npc2_like; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR003172; ML_dom.
DR InterPro; IPR033916; ML_Npc2-like.
DR InterPro; IPR039670; NPC2-like.
DR PANTHER; PTHR11306; PTHR11306; 1.
DR Pfam; PF02221; E1_DerP2_DerF2; 1.
DR SMART; SM00737; ML; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cholesterol metabolism;
KW Direct protein sequencing; Disease variant; Disulfide bond;
KW Endoplasmic reticulum; Glycoprotein; Lipid metabolism; Lipid transport;
KW Lysosome; Niemann-Pick disease; Reference proteome; Secreted; Signal;
KW Steroid metabolism; Sterol metabolism; Transport.
FT SIGNAL 1..19
FT /evidence="ECO:0000269|PubMed:11125141,
FT ECO:0000269|PubMed:17018531"
FT CHAIN 20..151
FT /note="NPC intracellular cholesterol transporter 2"
FT /id="PRO_0000019854"
FT MOD_RES 116
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0J0"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17018531,
FT ECO:0000269|PubMed:27551080, ECO:0007744|PDB:5KWY"
FT CARBOHYD 135
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:17018531,
FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:27551080,
FT ECO:0007744|PDB:5KWY"
FT DISULFID 27..140
FT /evidence="ECO:0000269|PubMed:27551080,
FT ECO:0007744|PDB:5KWY"
FT DISULFID 42..47
FT /evidence="ECO:0000269|PubMed:27551080,
FT ECO:0007744|PDB:5KWY"
FT DISULFID 93..99
FT /evidence="ECO:0000269|PubMed:27551080,
FT ECO:0007744|PDB:5KWY"
FT VAR_SEQ 122..147
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056459"
FT VARIANT 30
FT /note="V -> M (in NPC2; dbSNP:rs151220873)"
FT /evidence="ECO:0000269|PubMed:12955717"
FT /id="VAR_043303"
FT VARIANT 39
FT /note="V -> M (in NPC2; results in the synthesis of
FT functional recombinant proteins correctly targeted to
FT lysosomes; dbSNP:rs80358261)"
FT /evidence="ECO:0000269|PubMed:12447927,
FT ECO:0000269|PubMed:15937921"
FT /id="VAR_015848"
FT VARIANT 47
FT /note="C -> F (in NPC2; leads to the synthesis of misfolded
FT recombinant proteins that colocalized with an endoplasmic
FT reticulum marker; normally secreted but unable to correct
FT cholesterol storage in NPC2-deficient cells;
FT dbSNP:rs1555345993)"
FT /evidence="ECO:0000269|PubMed:12955717,
FT ECO:0000269|PubMed:15937921"
FT /id="VAR_043304"
FT VARIANT 67
FT /note="S -> P (in NPC2; leads to the synthesis of misfolded
FT recombinant proteins that colocalized with an endoplasmic
FT reticulum marker; normally secreted but unable to correct
FT cholesterol storage in NPC2-deficient cells;
FT dbSNP:rs11694)"
FT /evidence="ECO:0000269|PubMed:11567215,
FT ECO:0000269|PubMed:15937921"
FT /id="VAR_015849"
FT VARIANT 86
FT /note="P -> L (in dbSNP:rs4688)"
FT /id="VAR_011899"
FT VARIANT 93
FT /note="C -> F (in NPC2; leads to the synthesis of misfolded
FT recombinant proteins that colocalized with an endoplasmic
FT reticulum marker; normally secreted but unable to correct
FT cholesterol storage in NPC2-deficient cells;
FT dbSNP:rs143960270)"
FT /evidence="ECO:0000269|PubMed:12955717,
FT ECO:0000269|PubMed:15937921"
FT /id="VAR_043305"
FT VARIANT 99
FT /note="C -> R (in NPC2; leads to the synthesis of misfolded
FT recombinant proteins that colocalized with an endoplasmic
FT reticulum marker; normally secreted but unable to correct
FT cholesterol storage in NPC2-deficient cells;
FT dbSNP:rs80358264)"
FT /evidence="ECO:0000269|PubMed:15937921"
FT /id="VAR_043306"
FT VARIANT 120
FT /note="P -> S (in NPC2; unable to bind cholesterol;
FT dbSNP:rs104894458)"
FT /evidence="ECO:0000269|PubMed:16126423,
FT ECO:0000269|PubMed:18772377"
FT /id="VAR_043307"
FT STRAND 25..27
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 30..41
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 47..50
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 53..65
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 71..78
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 81..84
FT /evidence="ECO:0007829|PDB:5KWY"
FT HELIX 92..94
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 99..101
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 105..115
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 123..131
FT /evidence="ECO:0007829|PDB:5KWY"
FT STRAND 137..150
FT /evidence="ECO:0007829|PDB:5KWY"
SQ SEQUENCE 151 AA; 16570 MW; B141B611805DC910 CRC64;
MRFLAATFLL LALSTAAQAE PVQFKDCGSV DGVIKEVNVS PCPTQPCQLS KGQSYSVNVT
FTSNIQSKSS KAVVHGILMG VPVPFPIPEP DGCKSGINCP IQKDKTYSYL NKLPVKSEYP
SIKLVVEWQL QDDKNQSLFC WEIPVQIVSH L
