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Protein

Niemann-Pick C1 protein

Gene

Npc1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Intracellular cholesterol transporter which acts in concert with NPC2 and plays an important role in the egress of cholesterol from the endosomal/lysosomal compartment. Both NPC1 and NPC2 function as the cellular 'tag team duo' (TTD) to catalyze the mobilization of cholesterol within the multivesicular environment of the late endosome (LE) to effect egress through the limiting bilayer of the LE. NPC2 binds unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes and transfers it to the cholesterol-binding pocket of the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket and is exported from the limiting membrane of late endosomes/ lysosomes to the ER and plasma membrane by an unknown mechanism. Binds oxysterol with higher affinity than cholesterol. May play a role in vesicular trafficking in glia, a process that may be crucial for maintaining the structural and functional integrity of nerve terminals.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei41 – 411CholesterolBy similarity
Binding sitei79 – 791CholesterolBy similarity
Sitei108 – 1081Important for cholesterol bindingBy similarity

GO - Molecular functioni

  1. cholesterol binding Source: UniProtKB
  2. hedgehog receptor activity Source: InterPro

GO - Biological processi

  1. adult walking behavior Source: MGI
  2. autophagy Source: MGI
  3. bile acid metabolic process Source: UniProtKB
  4. cellular response to low-density lipoprotein particle stimulus Source: MGI
  5. cellular response to steroid hormone stimulus Source: MGI
  6. cholesterol efflux Source: MGI
  7. cholesterol homeostasis Source: UniProtKB
  8. cholesterol metabolic process Source: UniProtKB-KW
  9. cholesterol transport Source: UniProtKB
  10. endocytosis Source: MGI
  11. establishment of protein localization to membrane Source: MGI
  12. lysosomal transport Source: UniProtKB
  13. membrane raft organization Source: MGI
  14. negative regulation of cell death Source: Ensembl
  15. negative regulation of macroautophagy Source: MGI
  16. protein glycosylation Source: UniProtKB
  17. response to cadmium ion Source: Ensembl
  18. response to drug Source: MGI
Complete GO annotation...

Keywords - Biological processi

Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Names & Taxonomyi

Protein namesi
Recommended name:
Niemann-Pick C1 protein
Gene namesi
Name:Npc1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589 Componenti: Chromosome 18

Organism-specific databases

MGIiMGI:1097712. Npc1.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini23 – 269247LumenalSequence AnalysisAdd
BLAST
Transmembranei270 – 29021HelicalSequence AnalysisAdd
BLAST
Topological domaini291 – 35060CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei351 – 37121HelicalSequence AnalysisAdd
BLAST
Topological domaini372 – 621250LumenalSequence AnalysisAdd
BLAST
Transmembranei622 – 64221HelicalSequence AnalysisAdd
BLAST
Topological domaini643 – 65311CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei654 – 67421HelicalSequence AnalysisAdd
BLAST
Topological domaini675 – 6839LumenalSequence Analysis
Transmembranei684 – 70421HelicalSequence AnalysisAdd
BLAST
Topological domaini705 – 73026CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei731 – 75121HelicalSequence AnalysisAdd
BLAST
Topological domaini752 – 7598LumenalSequence Analysis
Transmembranei760 – 78021HelicalSequence AnalysisAdd
BLAST
Topological domaini781 – 83252CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei833 – 85321HelicalSequence AnalysisAdd
BLAST
Topological domaini854 – 1076223LumenalSequence AnalysisAdd
BLAST
Transmembranei1077 – 109418HelicalSequence AnalysisAdd
BLAST
Topological domaini1095 – 10973CytoplasmicSequence Analysis
Transmembranei1098 – 111821HelicalSequence AnalysisAdd
BLAST
Topological domaini1119 – 11235LumenalSequence Analysis
Transmembranei1124 – 114421HelicalSequence AnalysisAdd
BLAST
Topological domaini1145 – 11451CytoplasmicSequence Analysis
Transmembranei1146 – 116621HelicalSequence AnalysisAdd
BLAST
Topological domaini1167 – 119428LumenalSequence AnalysisAdd
BLAST
Transmembranei1195 – 121521HelicalSequence AnalysisAdd
BLAST
Topological domaini1216 – 122611CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei1227 – 124721HelicalSequence AnalysisAdd
BLAST
Topological domaini1248 – 127730LumenalSequence AnalysisAdd
BLAST

GO - Cellular componenti

  1. endoplasmic reticulum Source: UniProtKB
  2. endosome Source: MGI
  3. extracellular region Source: UniProtKB
  4. extracellular vesicular exosome Source: MGI
  5. Golgi apparatus Source: MGI
  6. integral component of plasma membrane Source: UniProtKB
  7. late endosome membrane Source: UniProtKB-SubCell
  8. lysosomal membrane Source: MGI
  9. lysosome Source: UniProtKB
  10. membrane Source: MGI
  11. membrane raft Source: MGI
  12. nuclear envelope Source: UniProtKB
  13. perinuclear region of cytoplasm Source: UniProtKB
  14. plasma membrane Source: MGI
  15. vesicle Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Endosome, Lysosome, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2222Sequence AnalysisAdd
BLAST
Chaini23 – 12771255Niemann-Pick C1 proteinPRO_0000023262Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi25 ↔ 74By similarity
Disulfide bondi31 ↔ 42By similarity
Disulfide bondi63 ↔ 109By similarity
Glycosylationi70 – 701N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi75 ↔ 113By similarity
Disulfide bondi97 ↔ 238By similarity
Disulfide bondi100 ↔ 160By similarity
Glycosylationi122 – 1221N-linked (GlcNAc...)Sequence Analysis
Glycosylationi137 – 1371N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi177 ↔ 184By similarity
Glycosylationi185 – 1851N-linked (GlcNAc...)Sequence Analysis
Glycosylationi222 – 2221N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi227 ↔ 243By similarity
Glycosylationi228 – 2281N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi240 ↔ 247By similarity
Glycosylationi414 – 4141N-linked (GlcNAc...)Sequence Analysis
Glycosylationi459 – 4591N-linked (GlcNAc...)Sequence Analysis
Glycosylationi478 – 4781N-linked (GlcNAc...)Sequence Analysis
Glycosylationi524 – 5241N-linked (GlcNAc...)Sequence Analysis
Glycosylationi868 – 8681N-linked (GlcNAc...)Sequence Analysis
Glycosylationi898 – 8981N-linked (GlcNAc...)Sequence Analysis
Glycosylationi916 – 9161N-linked (GlcNAc...)Sequence Analysis
Glycosylationi961 – 9611N-linked (GlcNAc...)Sequence Analysis
Glycosylationi968 – 9681N-linked (GlcNAc...)Sequence Analysis
Glycosylationi1063 – 10631N-linked (GlcNAc...)Sequence Analysis

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiO35604.
PaxDbiO35604.
PRIDEiO35604.

PTM databases

PhosphoSiteiO35604.

Expressioni

Tissue specificityi

Expressed predominantly in perisynaptic astrocytic glial processes. Also expressed in heart, spleen, lung, liver, skeletal muscle, kidney, testis.

Inductioni

Activated by the drugs progesterone and U-18666A which block cholesterol transport out of lysosomes and by the lysosomotropic agent NAH4CL.

Gene expression databases

CleanExiMM_NPC1.
ExpressionAtlasiO35604. baseline and differential.
GenevestigatoriO35604.

Interactioni

Subunit structurei

Interacts with TMEM97 (By similarity). Interacts (via the second lumenal domain) with NPC2 in a cholestrol-dependent manner.By similarity1 Publication

Structurei

3D structure databases

ProteinModelPortaliO35604.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini620 – 785166SSDPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni175 – 20531Important for cholesterol binding and cholesterol transfer from NPC1 to liposomesBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi1274 – 12774Di-leucine motif

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi249 – 25911Poly-ProAdd
BLAST

Domaini

A cysteine-rich N-terminal domain and a C-terminal domain containing a di-leucine motif necessary for lysosomal targeting are critical for mobilization of cholesterol from lysosomes.

Sequence similaritiesi

Belongs to the patched family.Curated
Contains 1 SSD (sterol-sensing) domain.PROSITE-ProRule annotation

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG149152.
GeneTreeiENSGT00760000119174.
HOGENOMiHOG000036674.
HOVERGENiHBG003913.
InParanoidiO35604.
KOiK12385.
OMAiAITETIC.
OrthoDBiEOG7QRQT0.
TreeFamiTF300416.

Family and domain databases

InterProiIPR004765. NP_C_type.
IPR003392. Patched.
IPR000731. SSD.
[Graphical view]
PfamiPF02460. Patched. 1 hit.
[Graphical view]
TIGRFAMsiTIGR00917. 2A060601. 1 hit.
PROSITEiPS50156. SSD. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

O35604-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGAHHPALGL LLLLLCPAQV FSQSCVWYGE CGIATGDKRY NCKYSGPPKP
60 70 80 90 100
LPKDGYDLVQ ELCPGLFFDN VSLCCDIQQL QTLKSNLQLP LQFLSRCPSC
110 120 130 140 150
FYNLMTLFCE LTCSPHQSQF LNVTATEDYF DPKTQENKTN VKELEYFVGQ
160 170 180 190 200
SFANAMYNAC RDVEAPSSNE KALGLLCGRD ARACNATNWI EYMFNKDNGQ
210 220 230 240 250
APFTIIPVFS DLSILGMEPM RNATKGCNES VDEVTGPCSC QDCSIVCGPK
260 270 280 290 300
PQPPPPPMPW RIWGLDAMYV IMWVTYVAFL FVFFGALLAV WCHRRRYFVS
310 320 330 340 350
EYTPIDSNIA FSVNSSDKGE ASCCDPLGAA FDDCLRRMFT KWGAFCVRNP
360 370 380 390 400
TCIIFFSLAF ITVCSSGLVF VQVTTNPVEL WSAPHSQARL EKEYFDKHFG
410 420 430 440 450
PFFRTEQLII QAPNTSVHIY EPYPAGADVP FGPPLNKEIL HQVLDLQIAI
460 470 480 490 500
ESITASYNNE TVTLQDICVA PLSPYNKNCT IMSVLNYFQN SHAVLDSQVG
510 520 530 540 550
DDFYIYADYH THFLYCVRAP ASLNDTSLLH GPCLGTFGGP VFPWLVLGGY
560 570 580 590 600
DDQNYNNATA LVITFPVNNY YNDTERLQRA WAWEKEFISF VKNYKNPNLT
610 620 630 640 650
ISFTAERSIE DELNRESNSD VFTVIISYVV MFLYISLALG HIQSCSRLLV
660 670 680 690 700
DSKISLGIAG ILIVLSSVAC SLGIFSYMGM PLTLIVIEVI PFLVLAVGVD
710 720 730 740 750
NIFILVQTYQ RDERLQEETL DQQLGRILGE VAPTMFLSSF SETSAFFFGA
760 770 780 790 800
LSSMPAVHTF SLFAGMAVLI DFLLQITCFV SLLGLDIKRQ EKNHLDILCC
810 820 830 840 850
VRGADDGQGS HASESYLFRF FKNYFAPLLL KDWLRPIVVA VFVGVLSFSV
860 870 880 890 900
AVVNKVDIGL DQSLSMPNDS YVIDYFKSLA QYLHSGPPVY FVLEEGYNYS
910 920 930 940 950
SRKGQNMVCG GMGCDNDSLV QQIFNAAELD TYTRVGFAPS SWIDDYFDWV
960 970 980 990 1000
SPQSSCCRLY NVTHQFCNAS VMDPTCVRCR PLTPEGKQRP QGKEFMKFLP
1010 1020 1030 1040 1050
MFLSDNPNPK CGKGGHAAYG SAVNIVGDDT YIGATYFMTY HTILKTSADY
1060 1070 1080 1090 1100
TDAMKKARLI ASNITETMRS KGSDYRVFPY SVFYVFYEQY LTIIDDTIFN
1110 1120 1130 1140 1150
LSVSLGSIFL VTLVVLGCEL WSAVIMCITI AMILVNMFGV MWLWGISLNA
1160 1170 1180 1190 1200
VSLVNLVMSC GISVEFCSHI TRAFTMSTKG SRVSRAEEAL AHMGSSVFSG
1210 1220 1230 1240 1250
ITLTKFGGIV VLAFAKSQIF EIFYFRMYLA MVLLGATHGL IFLPVLLSYI
1260 1270
GPSVNKAKRH TTYERYRGTE RERLLNF
Length:1,277
Mass (Da):142,885
Last modified:February 6, 2013 - v2
Checksum:i3B42230AAC86764E
GO

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti9 – 91G → GL in AAB63372 (PubMed:9211850).Curated
Sequence conflicti135 – 1351Q → P in AAB63372 (PubMed:9211850).Curated
Sequence conflicti147 – 1471F → Y in AAB63372 (PubMed:9211850).Curated
Sequence conflicti445 – 4451D → N in AAB63372 (PubMed:9211850).Curated
Sequence conflicti478 – 4781N → D in AAB63373 (PubMed:9211850).Curated
Sequence conflicti874 – 8752DY → AN in AAB63372 (PubMed:9211850).Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF003348 mRNA. Translation: AAB63372.1.
AF003349 Genomic DNA. Translation: AAB63373.1.
AC102096 Genomic DNA. No translation available.
AC102248 Genomic DNA. No translation available.
CH466622 Genomic DNA. Translation: EDL01560.1.
CCDSiCCDS29064.1.
PIRiT30188.
RefSeqiNP_032746.2. NM_008720.2.
UniGeneiMm.3484.

Genome annotation databases

EnsembliENSMUST00000025279; ENSMUSP00000025279; ENSMUSG00000024413.
GeneIDi18145.
KEGGimmu:18145.
UCSCiuc008ecb.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF003348 mRNA. Translation: AAB63372.1.
AF003349 Genomic DNA. Translation: AAB63373.1.
AC102096 Genomic DNA. No translation available.
AC102248 Genomic DNA. No translation available.
CH466622 Genomic DNA. Translation: EDL01560.1.
CCDSiCCDS29064.1.
PIRiT30188.
RefSeqiNP_032746.2. NM_008720.2.
UniGeneiMm.3484.

3D structure databases

ProteinModelPortaliO35604.
ModBaseiSearch...
MobiDBiSearch...

Chemistry

ChEMBLiCHEMBL2321610.

PTM databases

PhosphoSiteiO35604.

Proteomic databases

MaxQBiO35604.
PaxDbiO35604.
PRIDEiO35604.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000025279; ENSMUSP00000025279; ENSMUSG00000024413.
GeneIDi18145.
KEGGimmu:18145.
UCSCiuc008ecb.1. mouse.

Organism-specific databases

CTDi4864.
MGIiMGI:1097712. Npc1.

Phylogenomic databases

eggNOGiNOG149152.
GeneTreeiENSGT00760000119174.
HOGENOMiHOG000036674.
HOVERGENiHBG003913.
InParanoidiO35604.
KOiK12385.
OMAiAITETIC.
OrthoDBiEOG7QRQT0.
TreeFamiTF300416.

Miscellaneous databases

ChiTaRSiNpc1. mouse.
NextBioi293400.
PROiO35604.
SOURCEiSearch...

Gene expression databases

CleanExiMM_NPC1.
ExpressionAtlasiO35604. baseline and differential.
GenevestigatoriO35604.

Family and domain databases

InterProiIPR004765. NP_C_type.
IPR003392. Patched.
IPR000731. SSD.
[Graphical view]
PfamiPF02460. Patched. 1 hit.
[Graphical view]
TIGRFAMsiTIGR00917. 2A060601. 1 hit.
PROSITEiPS50156. SSD. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. "Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene."
    Loftus S.K., Morris J.A., Carstea E.D., Gu J.Z., Cummings C., Brown A., Ellison J., Ohno K., Rosenfeld M.A., Tagle D.A., Pentchev P.G., Pavan W.J.
    Science 277:232-235(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
  2. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    Strain: C57BL/6J.
  3. Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
    Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
  4. "Localization of Niemann-Pick C1 protein in astrocytes: implications for neuronal degeneration in Niemann-Pick type C disease."
    Patel S.C., Suresh S., Kumar U., Hu C.Y., Cooney A., Blanchette-Mackie E.J., Neufeld E.B., Patel R.C., Brady R.O., Patel Y.C., Pentchev P.G., Ong W.-Y.
    Proc. Natl. Acad. Sci. U.S.A. 96:1657-1662(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION.
  5. "Function of the Niemann-Pick type C proteins and their bypass by cyclodextrin."
    Vance J.E., Peake K.B.
    Curr. Opin. Lipidol. 22:204-209(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON FUNCTION.
  6. "Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding."
    Deffieu M.S., Pfeffer S.R.
    Proc. Natl. Acad. Sci. U.S.A. 108:18932-18936(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NPC2, SUBCELLULAR LOCATION, GLYCOSYLATION.

Entry informationi

Entry nameiNPC1_MOUSE
AccessioniPrimary (citable) accession number: O35604
Secondary accession number(s): G3X8W9, O35605
Entry historyi
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: February 6, 2013
Last modified: February 4, 2015
This is version 115 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.