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Protein

NPC intracellular cholesterol transporter 1

Gene

Npc1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -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 (PubMed:21896731, PubMed:22048958, PubMed:27551080). Unesterified cholesterol that has been released from LDLs in the lumen of the late endosomes/lysosomes is transferred by NPC2 to the cholesterol-binding pocket in the N-terminal domain of NPC1. Cholesterol binds to NPC1 with the hydroxyl group buried in the binding pocket (By similarity). 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 (Probable).By similarityCurated3 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei41CholesterolBy similarity1
Binding sitei79CholesterolBy similarity1
Sitei108Important for cholesterol bindingBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Biological processCholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Enzyme and pathway databases

ReactomeiR-MMU-8964038 LDL clearance

Chemistry databases

SwissLipidsiSLP:000000479

Names & Taxonomyi

Protein namesi
Recommended name:
NPC intracellular cholesterol transporter 1Imported
Alternative name(s):
Niemann-Pick C1 protein1 Publication
Gene namesi
Name:Npc1Imported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 18

Organism-specific databases

MGIiMGI:1097712 Npc1

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini23 – 269LumenalCuratedAdd BLAST247
Transmembranei270 – 290HelicalSequence analysisAdd BLAST21
Topological domaini291 – 350CytoplasmicCuratedAdd BLAST60
Transmembranei351 – 371HelicalSequence analysisAdd BLAST21
Topological domaini372 – 621LumenalCuratedAdd BLAST250
Transmembranei622 – 642HelicalSequence analysisAdd BLAST21
Topological domaini643 – 653CytoplasmicCuratedAdd BLAST11
Transmembranei654 – 674HelicalSequence analysisAdd BLAST21
Topological domaini675 – 683LumenalCurated9
Transmembranei684 – 704HelicalSequence analysisAdd BLAST21
Topological domaini705 – 730CytoplasmicCuratedAdd BLAST26
Transmembranei731 – 751HelicalSequence analysisAdd BLAST21
Topological domaini752 – 759LumenalCurated8
Transmembranei760 – 780HelicalSequence analysisAdd BLAST21
Topological domaini781 – 832CytoplasmicCuratedAdd BLAST52
Transmembranei833 – 853HelicalSequence analysisAdd BLAST21
Topological domaini854 – 1097LumenalCuratedAdd BLAST244
Transmembranei1098 – 1118HelicalSequence analysisAdd BLAST21
Topological domaini1119 – 1123CytoplasmicCurated5
Transmembranei1124 – 1144HelicalSequence analysisAdd BLAST21
Topological domaini1145LumenalCurated1
Transmembranei1146 – 1166HelicalSequence analysisAdd BLAST21
Topological domaini1167 – 1194CytoplasmicCuratedAdd BLAST28
Transmembranei1195 – 1215HelicalSequence analysisAdd BLAST21
Topological domaini1216 – 1226LumenalCuratedAdd BLAST11
Transmembranei1227 – 1247HelicalSequence analysisAdd BLAST21
Topological domaini1248 – 1277CytoplasmicCuratedAdd BLAST30

Keywords - Cellular componenti

Endosome, Lysosome, Membrane

Pathology & Biotechi

Involvement in diseasei

Defects in Npc1 cause a lysosomal storage disorder characterized by accumulation of cholesterol in lysosomes and impaired cholesterol homeostasis. Causes age-dependent loss of Purkinje cells, loss of body weight and leads then to ataxia and premature death at a median age of 72 days.2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi202 – 203PF → AA: Loss of function giving rise to cholesterol accumulation in kidney, liver, lung and spleen. No effect on lysosomal location. Mice display age-dependent weight loss, neurodegeneration with loss of Purkinje cells, ataxia and premature death at a median age of 84 days. 1 Publication2
Mutagenesisi378V → A: No effect on affinity for NPC2. 1 Publication1
Mutagenesisi404R → Q: Decreased affinity for NPC2. 1 Publication1
Mutagenesisi421E → A: Strongly decreased affinity for NPC2; when associated with 503-A-A-504. 1 Publication1
Mutagenesisi502 – 504DFY → AAA: Strongly decreased affinity for NPC2. 1 Publication3
Mutagenesisi503 – 504FY → AA: Decreased affinity for NPC2. Loss of function in cholesterol transport. No effect on subcellular location. Strongly decreased affinity for NPC2; when associated with A-421. 1 Publication2
Mutagenesisi518R → Q: Strongly decreased affinity for NPC2. No effect on lysosomal location. 1 Publication1
Mutagenesisi1005D → G in Npc1-nmf164; strongly decreased protein levels. Causes abnormal lipid storage in the spleen and liver, loss of cerebellar Purkinje cells and age-dependent ataxia. 1 Publication1

Chemistry databases

ChEMBLiCHEMBL2321610

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 22Sequence analysisAdd BLAST22
ChainiPRO_000002326223 – 1277NPC intracellular cholesterol transporter 1Add BLAST1255

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi25 ↔ 74By similarity
Disulfide bondi31 ↔ 42By similarity
Disulfide bondi63 ↔ 109By similarity
Glycosylationi70N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi75 ↔ 113By similarity
Disulfide bondi97 ↔ 238By similarity
Disulfide bondi100 ↔ 160By similarity
Glycosylationi122N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi137N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi177 ↔ 184By similarity
Glycosylationi185N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi222N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi227 ↔ 243By similarity
Glycosylationi228N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi240 ↔ 247By similarity
Glycosylationi414N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi459N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi468 ↔ 479By similarity
Glycosylationi478N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi516 ↔ 533By similarity
Glycosylationi524N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi868N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi898N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi909 ↔ 914By similarity
Glycosylationi916N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi956 ↔ 1011By similarity
Disulfide bondi957 ↔ 979By similarity
Glycosylationi961N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi967 ↔ 976By similarity
Glycosylationi968N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi1063N-linked (GlcNAc...) asparagineSequence analysis1

Post-translational modificationi

N-glycosylated.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

EPDiO35604
MaxQBiO35604
PaxDbiO35604
PeptideAtlasiO35604
PRIDEiO35604

PTM databases

iPTMnetiO35604
PhosphoSitePlusiO35604
SwissPalmiO35604

Expressioni

Tissue specificityi

Detected in liver (at protein level) (PubMed:21896731, PubMed:22048958). Ubiquitous (PubMed:9211850). Detected in adult heart, spleen, lung, liver, skeletal muscle, kidney, testis (PubMed:9211850).3 Publications

Gene expression databases

BgeeiENSMUSG00000024413 Expressed in 282 organ(s), highest expression level in secondary oocyte
CleanExiMM_NPC1
GenevisibleiO35604 MM

Interactioni

Subunit structurei

Interacts (via the second lumenal domain) with NPC2 (PubMed:22065762, PubMed:27551080). Interacts with TMEM97. Interacts with TIM1 (By similarity).By similarity2 Publications

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000025279

Structurei

3D structure databases

ProteinModelPortaliO35604
SMRiO35604
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini620 – 785SSDPROSITE-ProRule annotationAdd BLAST166

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni175 – 205Important for cholesterol binding and cholesterol transfer from NPC1 to liposomesBy similarityAdd BLAST31
Regioni1274 – 1277Required for location in lysosomesBy similarity4

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi1274 – 1277Di-leucine motifCurated4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi249 – 259Poly-ProAdd BLAST11

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.By similarity

Sequence similaritiesi

Belongs to the patched family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1933 Eukaryota
ENOG410XR54 LUCA
GeneTreeiENSGT00900000140845
HOGENOMiHOG000036674
HOVERGENiHBG003913
InParanoidiO35604
KOiK12385
OMAiYYFRMWL
OrthoDBiEOG091G00JD
TreeFamiTF300416

Family and domain databases

InterProiView protein in InterPro
IPR004765 NPC1-like
IPR032190 NPC1_N
IPR003392 Ptc/Disp
IPR000731 SSD
PfamiView protein in Pfam
PF16414 NPC1_N, 1 hit
PF02460 Patched, 1 hit
PF12349 Sterol-sensing, 1 hit
TIGRFAMsiTIGR00917 2A060601, 1 hit
PROSITEiView protein in PROSITE
PS50156 SSD, 1 hit

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)DescriptionActionsGraphical viewLength
Sequence conflicti9G → GL in AAB63372 (PubMed:9211850).Curated1
Sequence conflicti135Q → P in AAB63372 (PubMed:9211850).Curated1
Sequence conflicti147F → Y in AAB63372 (PubMed:9211850).Curated1
Sequence conflicti445D → N in AAB63372 (PubMed:9211850).Curated1
Sequence conflicti478N → D in AAB63373 (PubMed:9211850).Curated1
Sequence conflicti874 – 875DY → AN in AAB63372 (PubMed:9211850).Curated2

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

Similar proteinsi

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
SMRiO35604
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000025279

Chemistry databases

ChEMBLiCHEMBL2321610
SwissLipidsiSLP:000000479

PTM databases

iPTMnetiO35604
PhosphoSitePlusiO35604
SwissPalmiO35604

Proteomic databases

EPDiO35604
MaxQBiO35604
PaxDbiO35604
PeptideAtlasiO35604
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

eggNOGiKOG1933 Eukaryota
ENOG410XR54 LUCA
GeneTreeiENSGT00900000140845
HOGENOMiHOG000036674
HOVERGENiHBG003913
InParanoidiO35604
KOiK12385
OMAiYYFRMWL
OrthoDBiEOG091G00JD
TreeFamiTF300416

Enzyme and pathway databases

ReactomeiR-MMU-8964038 LDL clearance

Miscellaneous databases

ChiTaRSiNpc1 mouse
PROiPR:O35604
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000024413 Expressed in 282 organ(s), highest expression level in secondary oocyte
CleanExiMM_NPC1
GenevisibleiO35604 MM

Family and domain databases

InterProiView protein in InterPro
IPR004765 NPC1-like
IPR032190 NPC1_N
IPR003392 Ptc/Disp
IPR000731 SSD
PfamiView protein in Pfam
PF16414 NPC1_N, 1 hit
PF02460 Patched, 1 hit
PF12349 Sterol-sensing, 1 hit
TIGRFAMsiTIGR00917 2A060601, 1 hit
PROSITEiView protein in PROSITE
PS50156 SSD, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNPC1_MOUSE
AccessioniPrimary (citable) accession number: O35604
Secondary accession number(s): G3X8W9, O35605
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: February 6, 2013
Last modified: November 7, 2018
This is version 144 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
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Main funding by: National Institutes of Health

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