NPC2_MOUSE
ID NPC2_MOUSE Reviewed; 149 AA.
AC Q9Z0J0; Q3UB23;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=NPC intracellular cholesterol transporter 2 {ECO:0000312|MGI:MGI:1915213};
DE AltName: Full=Epididymal secretory protein E1;
DE Short=mE1 {ECO:0000303|PubMed:10863096};
DE AltName: Full=Niemann Pick type C2 protein homolog;
DE Flags: Precursor;
GN Name=Npc2 {ECO:0000312|MGI:MGI:1915213};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, GLYCOSYLATION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Embryo;
RX PubMed=10863096; DOI=10.1016/s0378-1119(00)00189-x;
RA Nakamura Y., Takayama N., Minamitani T., Ikuta T., Ariga H., Matsumoto K.;
RT "Primary structure, genomic organization and expression of the major
RT secretory protein of murine epididymis, ME1.";
RL Gene 251:55-62(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=BALB/cJ, C57BL/6J, and NOD;
RC TISSUE=Bone marrow, Small intestine, Spleen, Tongue, and Visual cortex;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Mammary gland;
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 [4]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-51; PHE-85; ASP-91;
RP LYS-94; VAL-115 AND TYR-119.
RX PubMed=12591949; DOI=10.1073/pnas.0530027100;
RA Ko D.C., Binkley J., Sidow A., Scott M.P.;
RT "The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein
RT is necessary to control lysosome cholesterol levels.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:2518-2525(2003).
RN [5]
RP FUNCTION.
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 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Lung, Pancreas, Spleen,
RC and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP ASP-91 AND VAL-115.
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 [8]
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 [9]
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 [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-116, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic fibroblast;
RX PubMed=23806337; DOI=10.1016/j.molcel.2013.06.001;
RA Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y.,
RA Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.;
RT "SIRT5-mediated lysine desuccinylation impacts diverse metabolic
RT pathways.";
RL Mol. Cell 50:919-930(2013).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF GLN-48; HIS-50; LYS-51; ASN-58; ILE-81;
RP VAL-83; ASP-91; LYS-94; ASP-104; GLU-127; ASP-132 AND LYS-134.
RX PubMed=26296895; DOI=10.1074/jbc.m115.667469;
RA McCauliff L.A., Xu Z., Li R., Kodukula S., Ko D.C., Scott M.P., Kahn P.C.,
RA Storch J.;
RT "Multiple Surface Regions on the Niemann-Pick C2 Protein Facilitate
RT Intracellular Cholesterol Transport.";
RL J. Biol. Chem. 290:27321-27331(2015).
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:12591949, PubMed:17018531,
CC PubMed:21315718, PubMed:26296895). Unesterified cholesterol that has
CC been released from LDLs in the lumen of the late endosomes/lysosomes is
CC transferred by NPC2 to the cholesterol-binding pocket in the N-terminal
CC domain of NPC1. May bind and mobilize cholesterol that is associated
CC with membranes. NPC2 binds cholesterol with a 1:1 stoichiometry. Can
CC bind a variety of sterols, including lathosterol, desmosterol and the
CC plant sterols stigmasterol and beta-sitosterol (By similarity). The
CC secreted form of NCP2 regulates biliary cholesterol secretion via
CC stimulation of ABCG5/ABCG8-mediated cholesterol transport
CC (PubMed:21315718). {ECO:0000250|UniProtKB:P61916,
CC ECO:0000269|PubMed:12591949, ECO:0000269|PubMed:17018531,
CC ECO:0000269|PubMed:21315718, ECO:0000269|PubMed:26296895}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol(in) = cholesterol(out); Xref=Rhea:RHEA:39747,
CC ChEBI:CHEBI:16113; Evidence={ECO:0000269|PubMed:26296895};
CC -!- SUBUNIT: Interacts with NPC1 (via the second lumenal domain) in a
CC cholestrol-dependent manner. Interacts with NUS1/NgBR, the interaction
CC stabilizes NCP2 and regulates cholesterol trafficking. Interacts with
CC DHDDS. Interacts with NEDD4L (via C2 domain). Interacts with NPC1L1.
CC {ECO:0000250|UniProtKB:P61916}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:10863096,
CC ECO:0000269|PubMed:12591949, ECO:0000269|PubMed:21315718}. Endoplasmic
CC reticulum {ECO:0000250|UniProtKB:P61916}. Lysosome
CC {ECO:0000250|UniProtKB:P61916}. Note=Interaction with cell-surface M6PR
CC mediates endocytosis and targeting to lysosomes.
CC {ECO:0000305|PubMed:12591949}.
CC -!- TISSUE SPECIFICITY: Detected in liver and bile (PubMed:21315718).
CC Detected in epididymis (at protein level). Detected in caput
CC epididymis, corpus epididymis, cauda epididymis and ovary
CC (PubMed:10863096). {ECO:0000269|PubMed:10863096,
CC ECO:0000269|PubMed:21315718}.
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 -!- PTM: N-glycosylated. {ECO:0000269|PubMed:10863096}.
CC -!- SIMILARITY: Belongs to the NPC2 family. {ECO:0000305}.
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DR EMBL; AB021289; BAA35183.1; -; mRNA.
DR EMBL; AK008603; BAB25771.1; -; mRNA.
DR EMBL; AK009127; BAB26090.1; -; mRNA.
DR EMBL; AK151067; BAE30083.1; -; mRNA.
DR EMBL; AK151133; BAE30141.1; -; mRNA.
DR EMBL; AK153020; BAE31654.1; -; mRNA.
DR EMBL; AK153203; BAE31803.1; -; mRNA.
DR EMBL; AK158624; BAE34585.1; -; mRNA.
DR EMBL; AK165263; BAE38111.1; -; mRNA.
DR EMBL; AK167869; BAE39885.1; -; mRNA.
DR EMBL; AK170327; BAE41721.1; -; mRNA.
DR EMBL; BC003471; AAH03471.1; -; mRNA.
DR EMBL; BC007190; AAH07190.1; -; mRNA.
DR CCDS; CCDS26050.1; -.
DR RefSeq; NP_075898.1; NM_023409.4.
DR AlphaFoldDB; Q9Z0J0; -.
DR SMR; Q9Z0J0; -.
DR BioGRID; 212567; 3.
DR IntAct; Q9Z0J0; 3.
DR MINT; Q9Z0J0; -.
DR STRING; 10090.ENSMUSP00000021668; -.
DR SwissLipids; SLP:000000473; -.
DR GlyGen; Q9Z0J0; 2 sites.
DR iPTMnet; Q9Z0J0; -.
DR PhosphoSitePlus; Q9Z0J0; -.
DR SwissPalm; Q9Z0J0; -.
DR EPD; Q9Z0J0; -.
DR jPOST; Q9Z0J0; -.
DR MaxQB; Q9Z0J0; -.
DR PaxDb; Q9Z0J0; -.
DR PeptideAtlas; Q9Z0J0; -.
DR PRIDE; Q9Z0J0; -.
DR ProteomicsDB; 293878; -.
DR Antibodypedia; 88; 320 antibodies from 34 providers.
DR DNASU; 67963; -.
DR Ensembl; ENSMUST00000021668; ENSMUSP00000021668; ENSMUSG00000021242.
DR GeneID; 67963; -.
DR KEGG; mmu:67963; -.
DR UCSC; uc007oft.1; mouse.
DR CTD; 10577; -.
DR MGI; MGI:1915213; Npc2.
DR VEuPathDB; HostDB:ENSMUSG00000021242; -.
DR eggNOG; KOG4063; Eukaryota.
DR GeneTree; ENSGT00390000006223; -.
DR HOGENOM; CLU_109192_1_0_1; -.
DR InParanoid; Q9Z0J0; -.
DR OMA; NLFCWEI; -.
DR OrthoDB; 1612792at2759; -.
DR PhylomeDB; Q9Z0J0; -.
DR TreeFam; TF317963; -.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR Reactome; R-MMU-8964038; LDL clearance.
DR BioGRID-ORCS; 67963; 7 hits in 73 CRISPR screens.
DR ChiTaRS; Npc2; mouse.
DR PRO; PR:Q9Z0J0; -.
DR Proteomes; UP000000589; Chromosome 12.
DR RNAct; Q9Z0J0; protein.
DR Bgee; ENSMUSG00000021242; Expressed in left lung lobe and 263 other tissues.
DR Genevisible; Q9Z0J0; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; HDA:BHF-UCL.
DR GO; GO:0005764; C:lysosome; IDA:MGI.
DR GO; GO:0015485; F:cholesterol binding; IMP:UniProtKB.
DR GO; GO:0120020; F:cholesterol transfer activity; ISO:MGI.
DR GO; GO:0019899; F:enzyme binding; ISO:MGI.
DR GO; GO:0032934; F:sterol binding; IBA:GO_Central.
DR GO; GO:0033344; P:cholesterol efflux; IMP:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; ISS:HGNC-UCL.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0030301; P:cholesterol transport; IMP:UniProtKB.
DR GO; GO:0032367; P:intracellular cholesterol transport; IMP:HGNC-UCL.
DR GO; GO:0032366; P:intracellular sterol transport; ISS:HGNC-UCL.
DR GO; GO:0009615; P:response to virus; IEA:Ensembl.
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 Acetylation; Cholesterol metabolism; Disulfide bond; Endoplasmic reticulum;
KW Glycoprotein; Lipid metabolism; Lipid transport; Lysosome;
KW Reference proteome; Secreted; Signal; Steroid metabolism;
KW Sterol metabolism; Transport.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..149
FT /note="NPC intracellular cholesterol transporter 2"
FT /id="PRO_0000019856"
FT MOD_RES 116
FT /note="N6-acetyllysine"
FT /evidence="ECO:0007744|PubMed:23806337"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 69
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 27..140
FT /evidence="ECO:0000250|UniProtKB:P61916"
FT DISULFID 42..47
FT /evidence="ECO:0000250|UniProtKB:P61916"
FT DISULFID 93..99
FT /evidence="ECO:0000250|UniProtKB:P61916"
FT MUTAGEN 48
FT /note="Q->A: Strongly decreased cholesterol export."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 50
FT /note="H->A: Strongly decreased cholesterol export."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 51
FT /note="K->A: Decreased cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:12591949,
FT ECO:0000269|PubMed:26296895"
FT MUTAGEN 58
FT /note="N->A: Decreased cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 81
FT /note="I->D: No effect on cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 83
FT /note="V->A: No effect on cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 85
FT /note="F->A: Loss of cholesterol binding. Abolishes
FT cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:12591949"
FT MUTAGEN 91
FT /note="D->A: Decreased cholesterol binding. Nearly
FT abolishes cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:12591949,
FT ECO:0000269|PubMed:26296895"
FT MUTAGEN 91
FT /note="D->A: No significant effect on biliary cholesterol
FT secretion."
FT /evidence="ECO:0000269|PubMed:21315718"
FT MUTAGEN 94
FT /note="K->A: Decreased cholesterol binding. Nearly
FT abolishes cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:12591949,
FT ECO:0000269|PubMed:26296895"
FT MUTAGEN 104
FT /note="D->A: Decreased cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 115
FT /note="V->F: Loss of cholesterol binding. Abolishes
FT cholesterol transport activity. Abolishes stimulation of
FT biliary cholesterol secretion."
FT /evidence="ECO:0000269|PubMed:12591949,
FT ECO:0000269|PubMed:21315718"
FT MUTAGEN 119
FT /note="Y->A: Loss of cholesterol binding. Abolishes
FT cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:12591949"
FT MUTAGEN 127
FT /note="E->A: Strongly decreased cholesterol export."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 132
FT /note="D->A: No effect on cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:26296895"
FT MUTAGEN 134
FT /note="K->A: No effect on cholesterol binding. Strongly
FT decreased cholesterol transport activity."
FT /evidence="ECO:0000269|PubMed:26296895"
SQ SEQUENCE 149 AA; 16442 MW; 6BDE56CF69791805 CRC64;
MRFLAATILL LALVAASQAE PLHFKDCGSK VGVIKEVNVS PCPTDPCQLH KGQSYSVNIT
FTSGTQSQNS TALVHGILEG IRVPFPIPEP DGCKSGINCP IQKDKVYSYL NKLPVKNEYP
SIKLVVEWKL EDDKKNNLFC WEIPVQITS
