NPCL1_MOUSE
ID NPCL1_MOUSE Reviewed; 1333 AA.
AC Q6T3U4; Q5SVX1;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2004, sequence version 1.
DT 03-AUG-2022, entry version 120.
DE RecName: Full=NPC1-like intracellular cholesterol transporter 1 {ECO:0000312|MGI:MGI:2685089};
DE AltName: Full=Niemann-Pick C1-like protein 1 {ECO:0000303|PubMed:14976318, ECO:0000303|PubMed:15671032};
DE Short=Npc1l1 {ECO:0000303|PubMed:14976318, ECO:0000303|PubMed:15671032};
DE Flags: Precursor;
GN Name=Npc1l1 {ECO:0000312|MGI:MGI:2685089};
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], FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=C57BL/6J;
RX PubMed=14976318; DOI=10.1126/science.1093131;
RA Altmann S.W., Davis H.R. Jr., Zhu L.-J., Yao X., Hoos L.M., Tetzloff G.,
RA Iyer S.P.N., Maguire M., Golovko A., Zeng M., Wang L., Murgolo N.,
RA Graziano M.P.;
RT "Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol
RT absorption.";
RL Science 303:1201-1204(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, AND INDUCTION.
RX PubMed=15173162; DOI=10.1074/jbc.m405817200;
RA Davis H.R. Jr., Zhu L.-J., Hoos L.M., Tetzloff G., Maguire M., Liu J.,
RA Yao X., Iyer S.P.N., Lam M.-H., Lund E.G., Detmers P.A., Graziano M.P.,
RA Altmann S.W.;
RT "Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and
RT cholesterol transporter and a key modulator of whole-body cholesterol
RT homeostasis.";
RL J. Biol. Chem. 279:33586-33592(2004).
RN [4]
RP TISSUE SPECIFICITY, FUNCTION, DISRUPTION PHENOTYPE, AND CATALYTIC ACTIVITY.
RX PubMed=15671032; DOI=10.1074/jbc.m409110200;
RA Davies J.P., Scott C., Oishi K., Liapis A., Ioannou Y.A.;
RT "Inactivation of NPC1L1 causes multiple lipid transport defects and
RT protects against diet-induced hypercholesterolemia.";
RL J. Biol. Chem. 280:12710-12720(2005).
RN [5]
RP INDUCTION.
RX PubMed=15604518; DOI=10.1194/jlr.m400400-jlr200;
RA van der Veen J.N., Kruit J.K., Havinga R., Baller J.F.W., Chimini G.,
RA Lestavel S., Staels B., Groot P.H.E., Groen A.K., Kuipers F.;
RT "Reduced cholesterol absorption upon PPARdelta activation coincides with
RT decreased intestinal expression of NPC1L1.";
RL J. Lipid Res. 46:526-534(2005).
RN [6]
RP INTERACTION WITH LIMA1.
RX PubMed=29880681; DOI=10.1126/science.aao6575;
RA Zhang Y.Y., Fu Z.Y., Wei J., Qi W., Baituola G., Luo J., Meng Y.J.,
RA Guo S.Y., Yin H., Jiang S.Y., Li Y.F., Miao H.H., Liu Y., Wang Y., Li B.L.,
RA Ma Y.T., Song B.L.;
RT "A LIMA1 variant promotes low plasma LDL cholesterol and decreases
RT intestinal cholesterol absorption.";
RL Science 360:1087-1092(2018).
CC -!- FUNCTION: Plays a major role in cholesterol homeostasis
CC (PubMed:14976318, PubMed:15173162, PubMed:15671032). Critical for the
CC uptake of cholesterol across the plasma membrane of the intestinal
CC enterocyte (PubMed:15173162, PubMed:15671032). Involved in plant sterol
CC absorption, it transports sitosterol, although at lower rates than
CC cholesterol (PubMed:15173162). May have a function in the transport of
CC multiple lipids and their homeostasis, thereby influencing lipid
CC metabolism regulation (PubMed:15671032). May be involved in caveolin
CC trafficking from the plasma membrane (PubMed:15671032). Acts as a
CC negative regulator of NPC2 and down-regulates its expression and
CC secretion by inhibiting its maturation and accelerating its degradation
CC (By similarity). {ECO:0000250|UniProtKB:Q9UHC9,
CC ECO:0000269|PubMed:14976318, ECO:0000269|PubMed:15173162,
CC ECO:0000269|PubMed:15671032}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol(in) = cholesterol(out); Xref=Rhea:RHEA:39747,
CC ChEBI:CHEBI:16113; Evidence={ECO:0000305|PubMed:15173162,
CC ECO:0000305|PubMed:15671032};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=sitosterol(out) = sitosterol(in); Xref=Rhea:RHEA:70723,
CC ChEBI:CHEBI:27693; Evidence={ECO:0000305|PubMed:15173162};
CC -!- SUBUNIT: Interacts with RAB11A, MYO5B and RAB11FIP2. Interaction with
CC RAB11A, MYO5B and RAB11FIP2 is required for proper transport to the
CC plasma membrane upon cholesterol depletion (By similarity). Interacts
CC with NPC2 (By similarity). Interacts with LIMA1 (PubMed:29880681).
CC {ECO:0000250, ECO:0000269|PubMed:29880681}.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane; Multi-pass membrane
CC protein. Cell membrane {ECO:0000250|UniProtKB:Q6T3U3}; Multi-pass
CC membrane protein. Note=Subfractionation of brush border membranes from
CC proximal enterocytes suggests considerable association with the apical
CC membrane fraction. Exists as a predominantly cell surface membrane
CC expressed protein.
CC -!- TISSUE SPECIFICITY: Expressed in small intestine, stomach and muscle,
CC along with detectable expression in lung, heart, gall bladder, brain,
CC testis, skin and liver. Expression in liver is extremely low.
CC {ECO:0000269|PubMed:14976318, ECO:0000269|PubMed:15671032}.
CC -!- INDUCTION: Cholesterol/cholate feeding resulted in down-regulation of
CC intestinal expression. Expression is decreased by 35% in the jejunum
CC upon PPARD activation. {ECO:0000269|PubMed:15173162,
CC ECO:0000269|PubMed:15604518}.
CC -!- PTM: Highly glycosylated. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Mice have multiple lipid transport defects and
CC have a protective effect against diet-induced hyperlipidemia. They have
CC also a deregulation of CAV1 transport and localization, suggesting that
CC the observed lipid transport defect may be the indirect result of an
CC inability of cells to properly target and/or regulate CAV1 expression.
CC {ECO:0000269|PubMed:15671032}.
CC -!- SIMILARITY: Belongs to the patched family. {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; AY437866; AAR97887.1; -; mRNA.
DR EMBL; AL607152; CAI24395.1; -; Genomic_DNA.
DR CCDS; CCDS24413.1; -.
DR AlphaFoldDB; Q6T3U4; -.
DR SMR; Q6T3U4; -.
DR STRING; 10090.ENSMUSP00000004505; -.
DR BindingDB; Q6T3U4; -.
DR ChEMBL; CHEMBL1075296; -.
DR iPTMnet; Q6T3U4; -.
DR PhosphoSitePlus; Q6T3U4; -.
DR jPOST; Q6T3U4; -.
DR MaxQB; Q6T3U4; -.
DR PaxDb; Q6T3U4; -.
DR PRIDE; Q6T3U4; -.
DR ProteomicsDB; 293948; -.
DR MGI; MGI:2685089; Npc1l1.
DR eggNOG; KOG1933; Eukaryota.
DR InParanoid; Q6T3U4; -.
DR PhylomeDB; Q6T3U4; -.
DR TreeFam; TF300416; -.
DR Reactome; R-MMU-8963678; Intestinal lipid absorption.
DR ChiTaRS; Npc1l1; mouse.
DR PRO; PR:Q6T3U4; -.
DR Proteomes; UP000000589; Unplaced.
DR RNAct; Q6T3U4; protein.
DR GO; GO:0016324; C:apical plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031526; C:brush border membrane; ISO:MGI.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0044214; C:spanning component of plasma membrane; ISO:MGI.
DR GO; GO:0015485; F:cholesterol binding; IBA:GO_Central.
DR GO; GO:1901363; F:heterocyclic compound binding; ISO:MGI.
DR GO; GO:0005319; F:lipid transporter activity; IEA:InterPro.
DR GO; GO:0031489; F:myosin V binding; ISO:MGI.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0031267; F:small GTPase binding; ISO:MGI.
DR GO; GO:0032934; F:sterol binding; IBA:GO_Central.
DR GO; GO:0071501; P:cellular response to sterol depletion; ISO:MGI.
DR GO; GO:0006695; P:cholesterol biosynthetic process; ISO:MGI.
DR GO; GO:0042632; P:cholesterol homeostasis; IMP:MGI.
DR GO; GO:0030301; P:cholesterol transport; IMP:UniProtKB.
DR GO; GO:0030299; P:intestinal cholesterol absorption; IMP:UniProtKB.
DR GO; GO:0042157; P:lipoprotein metabolic process; ISO:MGI.
DR GO; GO:0015918; P:sterol transport; IBA:GO_Central.
DR InterPro; IPR004765; NPC1-like.
DR InterPro; IPR032190; NPC1_N.
DR InterPro; IPR003392; Ptc/Disp.
DR InterPro; IPR000731; SSD.
DR Pfam; PF16414; NPC1_N; 1.
DR Pfam; PF02460; Patched; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR TIGRFAMs; TIGR00917; 2A060601; 1.
DR PROSITE; PS50156; SSD; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cholesterol metabolism; Disulfide bond; Glycoprotein;
KW Lipid metabolism; Membrane; Reference proteome; Signal; Steroid metabolism;
KW Sterol metabolism; Transmembrane; Transmembrane helix; Transport.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT CHAIN 21..1333
FT /note="NPC1-like intracellular cholesterol transporter 1"
FT /id="PRO_0000023267"
FT TOPO_DOM 21..284
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 285..305
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 306..352
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 353..373
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 374..632
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 633..653
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 654..665
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 666..686
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 687..696
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 697..717
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 718..742
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 743..763
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 764..776
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 777..797
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 798..846
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 847..867
FT /note="Helical; Name=8"
FT /evidence="ECO:0000255"
FT TOPO_DOM 868..1113
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1114..1134
FT /note="Helical; Name=9"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1135..1142
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1143..1163
FT /note="Helical; Name=10"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1164..1165
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1166..1186
FT /note="Helical; Name=11"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1187..1206
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 1207..1227
FT /note="Helical; Name=12"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1228..1242
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 1243..1263
FT /note="Helical; Name=13"
FT /evidence="ECO:0000255"
FT TOPO_DOM 1264..1333
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 632..797
FT /note="SSD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199"
FT DISULFID 32..90
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 38..56
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 77..125
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 91..129
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 113..254
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 116..172
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 189..197
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 243..259
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 256..263
FT /evidence="ECO:0000250|UniProtKB:Q9UHC9"
FT DISULFID 471..485
FT /evidence="ECO:0000250|UniProtKB:O15118"
FT DISULFID 525..542
FT /evidence="ECO:0000250|UniProtKB:O15118"
FT DISULFID 920..925
FT /evidence="ECO:0000250|UniProtKB:O15118"
FT DISULFID 967..1025
FT /evidence="ECO:0000250|UniProtKB:O15118"
FT DISULFID 981..990
FT /evidence="ECO:0000250|UniProtKB:O15118"
FT CONFLICT 476
FT /note="N -> K (in Ref. 2; CAI24395)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1333 AA; 147132 MW; 7771520D9B352735 CRC64;
MAAAWQGWLL WALLLNSAQG ELYTPTHKAG FCTFYEECGK NPELSGGLTS LSNISCLSNT
PARHVTGDHL ALLQRVCPRL YNGPNDTYAC CSTKQLVSLD SSLSITKALL TRCPACSENF
VSIHCHNTCS PDQSLFINVT RVVQRDPGQL PAVVAYEAFY QRSFAEKAYE SCSRVRIPAA
ASLAVGSMCG VYGSALCNAQ RWLNFQGDTG NGLAPLDITF HLLEPGQALA DGMKPLDGKI
TPCNESQGED SAACSCQDCA ASCPVIPPPP ALRPSFYMGR MPGWLALIII FTAVFVLLSV
VLVYLRVASN RNKNKTAGSQ EAPNLPRKRR FSPHTVLGRF FESWGTRVAS WPLTVLALSF
IVVIALSVGL TFIELTTDPV ELWSAPKSQA RKEKAFHDEH FGPFFRTNQI FVTAKNRSSY
KYDSLLLGPK NFSGILSLDL LQELLELQER LRHLQVWSHE AQRNISLQDI CYAPLNPHNT
SLTDCCVNSL LQYFQNNHTL LLLTANQTLN GQTSLVDWKD HFLYCANAPL TYKDGTALAL
SCIADYGAPV FPFLAVGGYQ GTDYSEAEAL IITFSINNYP ADDPRMAHAK LWEEAFLKEM
QSFQRSTADK FQIAFSAERS LEDEINRTTI QDLPVFAISY LIVFLYISLA LGSYSRWSRV
AVDSKATLGL GGVAVVLGAV VAAMGFYSYL GVPSSLVIIQ VVPFLVLAVG ADNIFIFVLE
YQRLPRMPGE QREAHIGRTL GSVAPSMLLC SLSEAICFFL GALTSMPAVR TFALTSGLAI
IFDFLLQMTA FVALLSLDSK RQEASRPDVV CCFSSRNLPP PKQKEGLLLC FFRKIYTPFL
LHRFIRPVVL LLFLVLFGAN LYLMCNISVG LDQDLALPKD SYLIDYFLFL NRYLEVGPPV
YFDTTSGYNF STEAGMNAIC SSAGCESFSL TQKIQYASEF PNQSYVAIAA SSWVDDFIDW
LTPSSSCCRI YTRGPHKDEF CPSTDTSFNC LKNCMNRTLG PVRPTTEQFH KYLPWFLNDT
PNIRCPKGGL AAYRTSVNLS SDGQIIASQF MAYHKPLRNS QDFTEALRAS RLLAANITAE
LRKVPGTDPN FEVFPYTISN VFYQQYLTVL PEGIFTLALC FVPTFVVCYL LLGLDIRSGI
LNLLSIIMIL VDTIGLMAVW GISYNAVSLI NLVTAVGMSV EFVSHITRSF AVSTKPTRLE
RAKDATIFMG SAVFAGVAMT NFPGILILGF AQAQLIQIFF FRLNLLITLL GLLHGLVFLP
VVLSYLGPDV NQALVLEEKL ATEAAMVSEP SCPQYPFPAD ANTSDYVNYG FNPEFIPEIN
AASSSLPKSD QKF
