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O35604

- NPC1_MOUSE

UniProt

O35604 - NPC1_MOUSE

Protein

Niemann-Pick C1 protein

Gene

Npc1

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 111 (01 Oct 2014)
      Sequence version 2 (06 Feb 2013)
      Previous versions | rss
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    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
    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

    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

    GO - Cellular componenti

    1. endoplasmic reticulum Source: UniProtKB
    2. endosome Source: MGI
    3. extracellular region Source: UniProtKB
    4. Golgi apparatus Source: MGI
    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

    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

    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.By similarity1 Publication

    Structurei

    3D structure databases

    ProteinModelPortaliO35604.
    SMRiO35604. Positions 16-249.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini23 – 269247LumenalSequence AnalysisAdd
    BLAST
    Topological domaini291 – 35060CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini372 – 621250LumenalSequence AnalysisAdd
    BLAST
    Topological domaini643 – 65311CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini675 – 6839LumenalSequence Analysis
    Topological domaini705 – 73026CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini752 – 7598LumenalSequence Analysis
    Topological domaini781 – 83252CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini854 – 1076223LumenalSequence AnalysisAdd
    BLAST
    Topological domaini1095 – 10973CytoplasmicSequence Analysis
    Topological domaini1119 – 11235LumenalSequence Analysis
    Topological domaini1145 – 11451CytoplasmicSequence Analysis
    Topological domaini1167 – 119428LumenalSequence AnalysisAdd
    BLAST
    Topological domaini1216 – 122611CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini1248 – 127730LumenalSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei270 – 29021HelicalSequence AnalysisAdd
    BLAST
    Transmembranei351 – 37121HelicalSequence AnalysisAdd
    BLAST
    Transmembranei622 – 64221HelicalSequence AnalysisAdd
    BLAST
    Transmembranei654 – 67421HelicalSequence AnalysisAdd
    BLAST
    Transmembranei684 – 70421HelicalSequence AnalysisAdd
    BLAST
    Transmembranei731 – 75121HelicalSequence AnalysisAdd
    BLAST
    Transmembranei760 – 78021HelicalSequence AnalysisAdd
    BLAST
    Transmembranei833 – 85321HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1077 – 109418HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1098 – 111821HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1124 – 114421HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1146 – 116621HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1195 – 121521HelicalSequence AnalysisAdd
    BLAST
    Transmembranei1227 – 124721HelicalSequence AnalysisAdd
    BLAST

    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.
    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

    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:
    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

    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: October 1, 2014
    This is version 111 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