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O35604

- NPC1_MOUSE

UniProt

O35604 - NPC1_MOUSE

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Protein
Niemann-Pick C1 protein
Gene
Npc1
Organism
Mus musculus (Mouse)
Status
Reviewed - 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 – 411Cholesterol By similarity
Binding sitei79 – 791Cholesterol By similarity
Sitei108 – 1081Important for cholesterol binding By similarity

GO - Molecular functioni

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

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. lysosomal transport Source: UniProtKB
  12. negative regulation of cell death Source: Ensembl
  13. negative regulation of macroautophagy Source: MGI
  14. protein glycosylation Source: UniProtKB
  15. response to cadmium ion Source: Ensembl
  16. 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: Chromosome 18

Organism-specific databases

MGIiMGI:1097712. Npc1.

Subcellular locationi

Late endosome membrane; Multi-pass membrane protein. Lysosome membrane; Multi-pass membrane protein 2 Publications

Topology

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

GO - Cellular componenti

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

Keywords - Cellular componenti

Endosome, Lysosome, Membrane

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2222 Reviewed prediction
Add
BLAST
Chaini23 – 12771255Niemann-Pick C1 protein
PRO_0000023262Add
BLAST

Amino acid modifications

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

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

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.
GenevestigatoriO35604.

Interactioni

Subunit structurei

Interacts with TMEM97 By similarity. Interacts (via the second lumenal domain) with NPC2 in a cholestrol-dependent manner.1 Publication

Structurei

3D structure databases

ProteinModelPortaliO35604.
SMRiO35604. Positions 16-249.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini620 – 785166SSD
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni175 – 20531Important for cholesterol binding and cholesterol transfer from NPC1 to liposomes By similarity
Add
BLAST

Motif

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

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi249 – 25911Poly-Pro
Add
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.

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiNOG149152.
GeneTreeiENSGT00680000099777.
HOGENOMiHOG000036674.
HOVERGENiHBG003913.
InParanoidiO35604.
KOiK12385.
OMAiPIHLPAE.
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

MGAHHPALGL LLLLLCPAQV FSQSCVWYGE CGIATGDKRY NCKYSGPPKP     50
LPKDGYDLVQ ELCPGLFFDN VSLCCDIQQL QTLKSNLQLP LQFLSRCPSC 100
FYNLMTLFCE LTCSPHQSQF LNVTATEDYF DPKTQENKTN VKELEYFVGQ 150
SFANAMYNAC RDVEAPSSNE KALGLLCGRD ARACNATNWI EYMFNKDNGQ 200
APFTIIPVFS DLSILGMEPM RNATKGCNES VDEVTGPCSC QDCSIVCGPK 250
PQPPPPPMPW RIWGLDAMYV IMWVTYVAFL FVFFGALLAV WCHRRRYFVS 300
EYTPIDSNIA FSVNSSDKGE ASCCDPLGAA FDDCLRRMFT KWGAFCVRNP 350
TCIIFFSLAF ITVCSSGLVF VQVTTNPVEL WSAPHSQARL EKEYFDKHFG 400
PFFRTEQLII QAPNTSVHIY EPYPAGADVP FGPPLNKEIL HQVLDLQIAI 450
ESITASYNNE TVTLQDICVA PLSPYNKNCT IMSVLNYFQN SHAVLDSQVG 500
DDFYIYADYH THFLYCVRAP ASLNDTSLLH GPCLGTFGGP VFPWLVLGGY 550
DDQNYNNATA LVITFPVNNY YNDTERLQRA WAWEKEFISF VKNYKNPNLT 600
ISFTAERSIE DELNRESNSD VFTVIISYVV MFLYISLALG HIQSCSRLLV 650
DSKISLGIAG ILIVLSSVAC SLGIFSYMGM PLTLIVIEVI PFLVLAVGVD 700
NIFILVQTYQ RDERLQEETL DQQLGRILGE VAPTMFLSSF SETSAFFFGA 750
LSSMPAVHTF SLFAGMAVLI DFLLQITCFV SLLGLDIKRQ EKNHLDILCC 800
VRGADDGQGS HASESYLFRF FKNYFAPLLL KDWLRPIVVA VFVGVLSFSV 850
AVVNKVDIGL DQSLSMPNDS YVIDYFKSLA QYLHSGPPVY FVLEEGYNYS 900
SRKGQNMVCG GMGCDNDSLV QQIFNAAELD TYTRVGFAPS SWIDDYFDWV 950
SPQSSCCRLY NVTHQFCNAS VMDPTCVRCR PLTPEGKQRP QGKEFMKFLP 1000
MFLSDNPNPK CGKGGHAAYG SAVNIVGDDT YIGATYFMTY HTILKTSADY 1050
TDAMKKARLI ASNITETMRS KGSDYRVFPY SVFYVFYEQY LTIIDDTIFN 1100
LSVSLGSIFL VTLVVLGCEL WSAVIMCITI AMILVNMFGV MWLWGISLNA 1150
VSLVNLVMSC GISVEFCSHI TRAFTMSTKG SRVSRAEEAL AHMGSSVFSG 1200
ITLTKFGGIV VLAFAKSQIF EIFYFRMYLA MVLLGATHGL IFLPVLLSYI 1250
GPSVNKAKRH TTYERYRGTE RERLLNF 1277
Length:1,277
Mass (Da):142,885
Last modified:February 6, 2013 - v2
Checksum:i3B42230AAC86764E
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti9 – 91G → GL in AAB63372. 1 Publication
Sequence conflicti135 – 1351Q → P in AAB63372. 1 Publication
Sequence conflicti147 – 1471F → Y in AAB63372. 1 Publication
Sequence conflicti445 – 4451D → N in AAB63372. 1 Publication
Sequence conflicti478 – 4781N → D in AAB63373. 1 Publication
Sequence conflicti874 – 8752DY → AN in AAB63372. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
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:
EMBL
GenBank
DDBJ
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 .
CCDSi CCDS29064.1.
PIRi T30188.
RefSeqi NP_032746.2. NM_008720.2.
UniGenei Mm.3484.

3D structure databases

ProteinModelPortali O35604.
SMRi O35604. Positions 16-249.
ModBasei Search...
MobiDBi Search...

Chemistry

ChEMBLi CHEMBL2321610.

PTM databases

PhosphoSitei O35604.

Proteomic databases

PaxDbi O35604.
PRIDEi O35604.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000025279 ; ENSMUSP00000025279 ; ENSMUSG00000024413 .
GeneIDi 18145.
KEGGi mmu:18145.
UCSCi uc008ecb.1. mouse.

Organism-specific databases

CTDi 4864.
MGIi MGI:1097712. Npc1.

Phylogenomic databases

eggNOGi NOG149152.
GeneTreei ENSGT00680000099777.
HOGENOMi HOG000036674.
HOVERGENi HBG003913.
InParanoidi O35604.
KOi K12385.
OMAi PIHLPAE.
OrthoDBi EOG7QRQT0.
TreeFami TF300416.

Miscellaneous databases

ChiTaRSi NPC1. mouse.
NextBioi 293400.
PROi O35604.
SOURCEi Search...

Gene expression databases

CleanExi MM_NPC1.
Genevestigatori O35604.

Family and domain databases

InterProi IPR004765. NP_C_type.
IPR003392. Patched.
IPR000731. SSD.
[Graphical view ]
Pfami PF02460. Patched. 1 hit.
[Graphical view ]
TIGRFAMsi TIGR00917. 2A060601. 1 hit.
PROSITEi PS50156. SSD. 1 hit.
[Graphical view ]
ProtoNeti Search...

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(1997) [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 (JUL-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(1999) [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(2011) [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(2011) [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: July 9, 2014
This is version 110 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