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UniProtKB - P61916 (NPC2_HUMAN)

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Protein

NPC intracellular cholesterol transporter 2

Gene

NPC2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Intracellular cholesterol transporter which acts in concert with NPC1 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. The secreted form of NCP2 regulates biliary cholesterol secretion via stimulation of ABCG5/ABCG8-mediated cholesterol transport.3 Publications

GO - Molecular functioni

  • cholesterol binding Source: UniProtKB
  • cholesterol transporter activity Source: BHF-UCL
  • enzyme binding Source: UniProtKB
View the complete GO annotation on QuickGO ...

GO - Biological processi

  • cholesterol efflux Source: BHF-UCL
  • cholesterol homeostasis Source: UniProtKB
  • cholesterol metabolic process Source: UniProtKB-KW
  • cholesterol transport Source: UniProtKB
  • glycolipid transport Source: HGNC
  • intracellular cholesterol transport Source: UniProtKB
  • intracellular sterol transport Source: HGNC
  • low-density lipoprotein particle clearance Source: Reactome
  • neutrophil degranulation Source: Reactome
  • phospholipid transport Source: HGNC
  • regulation of isoprenoid metabolic process Source: UniProtKB
  • response to virus Source: UniProtKB
View the complete GO annotation on QuickGO ...

Keywordsi

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

Enzyme and pathway databases

ReactomeiR-HSA-6798695 Neutrophil degranulation
R-HSA-8964038 LDL clearance

Protein family/group databases

TCDBi2.A.6.6.1 the resistance-nodulation-cell division (rnd) superfamily

Chemistry databases

SwissLipidsiSLP:000000475

Names & Taxonomyi

Protein namesi
Recommended name:
NPC intracellular cholesterol transporter 2Imported
Alternative name(s):
Epididymal secretory protein E1
Human epididymis-specific protein 1
Short name:
He1
Niemann-Pick disease type C2 protein
Gene namesi
Name:NPC2Imported
Synonyms:HE1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 14

Organism-specific databases

EuPathDBiHostDB:ENSG00000119655.8
HGNCiHGNC:14537 NPC2
MIMi601015 gene
neXtProtiNX_P61916

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

Keywords - Cellular componenti

Endoplasmic reticulum, Lysosome, Secreted

Pathology & Biotechi

Involvement in diseasei

Niemann-Pick disease C2 (NPC2)6 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA lysosomal storage disorder that affects the viscera and the central nervous system. It is due to defective intracellular processing and transport of low-density lipoprotein derived cholesterol. It causes accumulation of cholesterol in lysosomes, with delayed induction of cholesterol homeostatic reactions. Niemann-Pick disease type C2 has a highly variable clinical phenotype. Clinical features include variable hepatosplenomegaly and severe progressive neurological dysfunction such as ataxia, dystonia and dementia. The age of onset can vary from infancy to late adulthood.
See also OMIM:607625
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04330330V → M in NPC2. 1 PublicationCorresponds to variant dbSNP:rs151220873EnsemblClinVar.1
Natural variantiVAR_01584839V → M in NPC2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes. 1 PublicationCorresponds to variant dbSNP:rs80358261EnsemblClinVar.1
Natural variantiVAR_04330447C → F in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 2 Publications1
Natural variantiVAR_01584967S → P in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 2 PublicationsCorresponds to variant dbSNP:rs11694EnsemblClinVar.1
Natural variantiVAR_04330593C → F in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 2 PublicationsCorresponds to variant dbSNP:rs143960270Ensembl.1
Natural variantiVAR_04330699C → R in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 1 PublicationCorresponds to variant dbSNP:rs80358264EnsemblClinVar.1
Natural variantiVAR_043307120P → S in NPC2. 1 PublicationCorresponds to variant dbSNP:rs104894458EnsemblClinVar.1

Keywords - Diseasei

Disease mutation, Niemann-Pick disease

Organism-specific databases

DisGeNETi10577
GeneReviewsiNPC2
MalaCardsiNPC2
MIMi607625 phenotype
OpenTargetsiENSG00000119655
Orphaneti216986 Niemann-Pick disease type C, adult neurologic onset
216981 Niemann-Pick disease type C, juvenile neurologic onset
216978 Niemann-Pick disease type C, late infantile neurologic onset
216975 Niemann-Pick disease type C, severe early infantile neurologic onset
216972 Niemann-Pick disease type C, severe perinatal form
PharmGKBiPA31700

Polymorphism and mutation databases

BioMutaiNPC2
DMDMi48429027

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 191 PublicationAdd BLAST19
ChainiPRO_000001985420 – 151NPC intracellular cholesterol transporter 2Add BLAST132

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi27 ↔ 140By similarity
Disulfide bondi42 ↔ 47By similarity
Glycosylationi58N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi93 ↔ 99By similarity
Modified residuei116N6-acetyllysineBy similarity1
Glycosylationi135N-linked (GlcNAc...) asparagine2 Publications1

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein

Proteomic databases

EPDiP61916
MaxQBiP61916
PaxDbiP61916
PeptideAtlasiP61916
PRIDEiP61916
ProteomicsDBi57337
TopDownProteomicsiP61916-2 [P61916-2]

PTM databases

iPTMnetiP61916
PhosphoSitePlusiP61916

Miscellaneous databases

PMAP-CutDBiP61916

Expressioni

Tissue specificityi

Epididymis.1 Publication

Inductioni

Down-regulated in response to enterovirus 71 (EV71) infection.1 Publication

Gene expression databases

BgeeiENSG00000119655
CleanExiHS_NPC2
ExpressionAtlasiP61916 baseline and differential
GenevisibleiP61916 HS

Organism-specific databases

HPAiHPA000835

Interactioni

Subunit structurei

Interacts with NUS1/NgBR, the interaction stabilizes NCP2 and regulates cholesterol trafficking. Interacts with DHDDS. Interacts with NPC1 (via the second lumenal domain) in a cholestrol-dependent manner (By similarity). Interacts with NEDD4L (via C2 domain) (By similarity). Interacts with NPC1L1.By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
NEGR1Q7Z3B19EBI-2368946,EBI-4314838

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi115828, 29 interactors
IntActiP61916, 5 interactors
MINTiP61916
STRINGi9606.ENSP00000451112

Structurei

Secondary structure

1151
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi25 – 27Combined sources3
Beta strandi30 – 41Combined sources12
Beta strandi47 – 50Combined sources4
Beta strandi53 – 65Combined sources13
Beta strandi71 – 78Combined sources8
Beta strandi81 – 84Combined sources4
Helixi92 – 94Combined sources3
Beta strandi99 – 101Combined sources3
Beta strandi105 – 115Combined sources11
Beta strandi123 – 131Combined sources9
Beta strandi137 – 150Combined sources14

3D structure databases

ProteinModelPortaliP61916
SMRiP61916
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the NPC2 family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG4063 Eukaryota
ENOG4111Q8S LUCA
GeneTreeiENSGT00390000006223
HOGENOMiHOG000007181
HOVERGENiHBG018181
InParanoidiP61916
KOiK13443
PhylomeDBiP61916
TreeFamiTF317963

Family and domain databases

CDDicd00916 Npc2_like, 1 hit
InterProiView protein in InterPro
IPR014756 Ig_E-set
IPR003172 ML_dom
IPR033916 ML_Npc2-like
PfamiView protein in Pfam
PF02221 E1_DerP2_DerF2, 1 hit
SMARTiView protein in SMART
SM00737 ML, 1 hit
SUPFAMiSSF81296 SSF81296, 1 hit

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: P61916-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MRFLAATFLL LALSTAAQAE PVQFKDCGSV DGVIKEVNVS PCPTQPCQLS 
        60         70         80         90        100
KGQSYSVNVT FTSNIQSKSS KAVVHGILMG VPVPFPIPEP DGCKSGINCP 
       110        120        130        140        150
IQKDKTYSYL NKLPVKSEYP SIKLVVEWQL QDDKNQSLFC WEIPVQIVSH 

L
Length:151
Mass (Da):16,570
Last modified:June 7, 2004 - v1
Checksum:iB141B611805DC910
GO
Isoform 2 (identifier: P61916-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     122-147: Missing.

Note: No experimental confirmation available.
Show »
Length:125
Mass (Da):13,416
Checksum:iE94FCACA6B6691FE
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04330330V → M in NPC2. 1 PublicationCorresponds to variant dbSNP:rs151220873EnsemblClinVar.1
Natural variantiVAR_01584839V → M in NPC2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes. 1 PublicationCorresponds to variant dbSNP:rs80358261EnsemblClinVar.1
Natural variantiVAR_04330447C → F in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 2 Publications1
Natural variantiVAR_01584967S → P in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 2 PublicationsCorresponds to variant dbSNP:rs11694EnsemblClinVar.1
Natural variantiVAR_01189986P → L. Corresponds to variant dbSNP:rs4688Ensembl.1
Natural variantiVAR_04330593C → F in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 2 PublicationsCorresponds to variant dbSNP:rs143960270Ensembl.1
Natural variantiVAR_04330699C → R in NPC2; leads to the synthesis of misfolded recombinant proteins that colocalized with an endoplasmic reticulum marker; normally secreted but unable to correct cholesterol storage in NPC2-deficient cells. 1 PublicationCorresponds to variant dbSNP:rs80358264EnsemblClinVar.1
Natural variantiVAR_043307120P → S in NPC2. 1 PublicationCorresponds to variant dbSNP:rs104894458EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_056459122 – 147Missing in isoform 2. 1 PublicationAdd BLAST26

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X67698 mRNA Translation: CAA47928.1
AK298975 mRNA Translation: BAG61069.1
AC005479 Genomic DNA No translation available.
BC002532 mRNA Translation: AAH02532.1
CCDSiCCDS32121.1 [P61916-1]
PIRiI38365
RefSeqiNP_006423.1, NM_006432.3 [P61916-1]
UniGeneiHs.433222

Genome annotation databases

EnsembliENST00000541064; ENSP00000442488; ENSG00000119655 [P61916-2]
ENST00000555619; ENSP00000451112; ENSG00000119655 [P61916-1]
GeneIDi10577
KEGGihsa:10577
UCSCiuc001xpy.4 human [P61916-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiNPC2_HUMAN
AccessioniPrimary (citable) accession number: P61916
Secondary accession number(s): B4DQV7, Q15668, Q29413
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 7, 2004
Last sequence update: June 7, 2004
Last modified: June 20, 2018
This is version 140 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 14
    Human chromosome 14: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. SIMILARITY comments
    Index of protein domains and families

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