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P61916

- NPC2_HUMAN

UniProt

P61916 - NPC2_HUMAN

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Protein
Epididymal secretory protein E1
Gene
NPC2, HE1
Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5 - 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

  1. cholesterol binding Source: UniProtKB
  2. enzyme binding Source: UniProtKB
  3. protein binding Source: UniProtKB

GO - Biological processi

  1. cholesterol efflux Source: BHF-UCL
  2. cholesterol homeostasis Source: UniProtKB
  3. cholesterol metabolic process Source: UniProtKB-KW
  4. cholesterol transport Source: UniProtKB
  5. glycolipid transport Source: HGNC
  6. intracellular cholesterol transport Source: UniProtKB
  7. intracellular sterol transport Source: HGNC
  8. phospholipid transport Source: HGNC
  9. regulation of isoprenoid metabolic process Source: UniProtKB
  10. response to virus Source: UniProtKB
Complete GO annotation...

Keywords - Biological processi

Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Protein family/group databases

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

Names & Taxonomyi

Protein namesi
Recommended name:
Epididymal secretory protein E1
Alternative name(s):
Human epididymis-specific protein 1
Short name:
He1
Niemann-Pick disease type C2 protein
Gene namesi
Name:NPC2
Synonyms:HE1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 14

Organism-specific databases

HGNCiHGNC:14537. NPC2.

Subcellular locationi

Secreted. Endoplasmic reticulum. Lysosome 1 Publication

GO - Cellular componenti

  1. endoplasmic reticulum Source: UniProtKB-SubCell
  2. extracellular vesicular exosome Source: UniProt
  3. lysosome Source: HGNC
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Lysosome, Secreted

Pathology & Biotechi

Involvement in diseasei

Niemann-Pick disease C2 (NPC2) [MIM:607625]: A 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.
Note: The disease is caused by mutations affecting the gene represented in this entry.6 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti30 – 301V → M in NPC2. 1 Publication
Corresponds to variant rs151220873 [ dbSNP | Ensembl ].
VAR_043303
Natural varianti39 – 391V → M in NPC2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes. 1 Publication
VAR_015848
Natural varianti47 – 471C → 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 Publications
VAR_043304
Natural varianti67 – 671S → 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 Publications
Corresponds to variant rs11694 [ dbSNP | Ensembl ].
VAR_015849
Natural varianti93 – 931C → 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 Publications
VAR_043305
Natural varianti99 – 991C → 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 Publication
VAR_043306
Natural varianti120 – 1201P → S in NPC2. 1 Publication
VAR_043307

Keywords - Diseasei

Disease mutation, Niemann-Pick disease

Organism-specific databases

MIMi607625. phenotype.
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.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 19191 Publication
Add
BLAST
Chaini20 – 151132Epididymal secretory protein E1
PRO_0000019854Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi27 ↔ 140 By similarity
Disulfide bondi42 ↔ 47 By similarity
Glycosylationi58 – 581N-linked (GlcNAc...)1 Publication
Disulfide bondi93 ↔ 99 By similarity
Modified residuei116 – 1161N6-acetyllysine By similarity
Glycosylationi135 – 1351N-linked (GlcNAc...)2 Publications

Keywords - PTMi

Acetylation, Disulfide bond, Glycoprotein

Proteomic databases

MaxQBiP61916.
PaxDbiP61916.
PeptideAtlasiP61916.
PRIDEiP61916.

PTM databases

PhosphoSiteiP61916.

Miscellaneous databases

PMAP-CutDBP61916.

Expressioni

Tissue specificityi

Epididymis.1 Publication

Inductioni

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

Gene expression databases

ArrayExpressiP61916.
BgeeiP61916.
CleanExiHS_NPC2.
GenevestigatoriP61916.

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 NPC1L1.4 Publications

Protein-protein interaction databases

BioGridi115828. 12 interactions.
IntActiP61916. 1 interaction.
STRINGi9606.ENSP00000238633.

Structurei

3D structure databases

ProteinModelPortaliP61916.
SMRiP61916. Positions 20-147.

Family & Domainsi

Sequence similaritiesi

Belongs to the NPC2 family.

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiNOG281614.
HOGENOMiHOG000007181.
HOVERGENiHBG018181.
InParanoidiP61916.
KOiK13443.
PhylomeDBiP61916.
TreeFamiTF317963.

Family and domain databases

Gene3Di2.60.40.770. 1 hit.
InterProiIPR014756. Ig_E-set.
IPR003172. ML_dom.
[Graphical view]
PfamiPF02221. E1_DerP2_DerF2. 1 hit.
[Graphical view]
SMARTiSM00737. ML. 1 hit.
[Graphical view]
SUPFAMiSSF81296. SSF81296. 1 hit.

Sequencei

Sequence statusi: Complete.

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

P61916-1 [UniParc]FASTAAdd to Basket

« Hide

MRFLAATFLL LALSTAAQAE PVQFKDCGSV DGVIKEVNVS PCPTQPCQLS    50
KGQSYSVNVT FTSNIQSKSS KAVVHGILMG VPVPFPIPEP DGCKSGINCP 100
IQKDKTYSYL NKLPVKSEYP SIKLVVEWQL QDDKNQSLFC WEIPVQIVSH 150
L 151
Length:151
Mass (Da):16,570
Last modified:June 7, 2004 - v1
Checksum:iB141B611805DC910
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti30 – 301V → M in NPC2. 1 Publication
Corresponds to variant rs151220873 [ dbSNP | Ensembl ].
VAR_043303
Natural varianti39 – 391V → M in NPC2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes. 1 Publication
VAR_015848
Natural varianti47 – 471C → 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 Publications
VAR_043304
Natural varianti67 – 671S → 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 Publications
Corresponds to variant rs11694 [ dbSNP | Ensembl ].
VAR_015849
Natural varianti86 – 861P → L.
Corresponds to variant rs4688 [ dbSNP | Ensembl ].
VAR_011899
Natural varianti93 – 931C → 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 Publications
VAR_043305
Natural varianti99 – 991C → 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 Publication
VAR_043306
Natural varianti120 – 1201P → S in NPC2. 1 Publication
VAR_043307

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X67698 mRNA. Translation: CAA47928.1.
BC002532 mRNA. Translation: AAH02532.1.
CCDSiCCDS32121.1.
PIRiI38365.
RefSeqiNP_006423.1. NM_006432.3.
UniGeneiHs.433222.

Genome annotation databases

EnsembliENST00000555619; ENSP00000451112; ENSG00000119655.
GeneIDi10577.
KEGGihsa:10577.
UCSCiuc001xpy.3. human.

Polymorphism databases

DMDMi48429027.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

Niemann-Pick type C disease gene variation database

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
X67698 mRNA. Translation: CAA47928.1 .
BC002532 mRNA. Translation: AAH02532.1 .
CCDSi CCDS32121.1.
PIRi I38365.
RefSeqi NP_006423.1. NM_006432.3.
UniGenei Hs.433222.

3D structure databases

ProteinModelPortali P61916.
SMRi P61916. Positions 20-147.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 115828. 12 interactions.
IntActi P61916. 1 interaction.
STRINGi 9606.ENSP00000238633.

Protein family/group databases

TCDBi 2.A.6.6.1. the resistance-nodulation-cell division (rnd) superfamily.

PTM databases

PhosphoSitei P61916.

Polymorphism databases

DMDMi 48429027.

Proteomic databases

MaxQBi P61916.
PaxDbi P61916.
PeptideAtlasi P61916.
PRIDEi P61916.

Protocols and materials databases

DNASUi 10577.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000555619 ; ENSP00000451112 ; ENSG00000119655 .
GeneIDi 10577.
KEGGi hsa:10577.
UCSCi uc001xpy.3. human.

Organism-specific databases

CTDi 10577.
GeneCardsi GC14M074943.
GeneReviewsi NPC2.
HGNCi HGNC:14537. NPC2.
HPAi HPA000835.
MIMi 601015. gene.
607625. phenotype.
neXtProti NX_P61916.
Orphaneti 216986. 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.
PharmGKBi PA31700.
GenAtlasi Search...

Phylogenomic databases

eggNOGi NOG281614.
HOGENOMi HOG000007181.
HOVERGENi HBG018181.
InParanoidi P61916.
KOi K13443.
PhylomeDBi P61916.
TreeFami TF317963.

Miscellaneous databases

ChiTaRSi NPC2. human.
GenomeRNAii 10577.
NextBioi 40145.
PMAP-CutDB P61916.
PROi P61916.
SOURCEi Search...

Gene expression databases

ArrayExpressi P61916.
Bgeei P61916.
CleanExi HS_NPC2.
Genevestigatori P61916.

Family and domain databases

Gene3Di 2.60.40.770. 1 hit.
InterProi IPR014756. Ig_E-set.
IPR003172. ML_dom.
[Graphical view ]
Pfami PF02221. E1_DerP2_DerF2. 1 hit.
[Graphical view ]
SMARTi SM00737. ML. 1 hit.
[Graphical view ]
SUPFAMi SSF81296. SSF81296. 1 hit.
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Region-specific variation of gene expression in the human epididymis as revealed by in situ hybridization with tissue-specific cDNAs."
    Krull N., Ivell R., Osterhoff C., Kirchhoff C.
    Mol. Reprod. Dev. 34:16-24(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    Tissue: Epididymis.
  2. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Tissue: Ovary.
  3. "NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols."
    Liou H.L., Dixit S.S., Xu S., Tint G.S., Stock A.M., Lobel P.
    J. Biol. Chem. 281:36710-36723(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEIN SEQUENCE OF N-TERMINUS, GLYCOSYLATION AT ASN-58 AND ASN-135, FUNCTION.
    Tissue: Brain.
  4. "Identification of HE1 as the second gene of Niemann-Pick C disease."
    Naureckiene S., Sleat D.E., Lackland H., Fensom A., Vanier M.T., Wattiaux R., Jadot M., Lobel P.
    Science 290:2298-2301(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INVOLVEMENT IN NPC2.
  5. "In vivo interaction between the human dehydrodolichyl diphosphate synthase and the Niemann-Pick C2 protein revealed by a yeast two-hybrid system."
    Kharel Y., Takahashi S., Yamashita S., Koyama T.
    Biochem. Biophys. Res. Commun. 318:198-203(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH DHDDS.
  6. "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells reveal differential cellular gene expression in response to enterovirus 71 infection."
    Leong W.F., Chow V.T.
    Cell. Microbiol. 8:565-580(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INDUCTION, IDENTIFICATION BY MASS SPECTROMETRY.
  7. "Regulation of sterol transport between membranes and NPC2."
    Xu Z., Farver W., Kodukula S., Storch J.
    Biochemistry 47:11134-11143(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  8. "NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes."
    Infante R.E., Wang M.L., Radhakrishnan A., Kwon H.J., Brown M.S., Goldstein J.L.
    Proc. Natl. Acad. Sci. U.S.A. 105:15287-15292(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  9. Cited for: INTERACTION WITH NEDD4L, TISSUE SPECIFICITY.
  10. "Nogo-B receptor stabilizes Niemann-Pick type C2 protein and regulates intracellular cholesterol trafficking."
    Harrison K.D., Miao R.Q., Fernandez-Hernando C., Suarez Y., Davalos A., Sessa W.C.
    Cell Metab. 10:208-218(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: SUBCELLULAR LOCATION, INTERACTION WITH NUS1.
  11. "Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
    Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
    J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-135.
    Tissue: Liver.
  12. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
  13. "Novel function of Niemann-Pick C1-like 1 as a negative regulator of Niemann-Pick C2 protein."
    Yamanashi Y., Takada T., Shoda J., Suzuki H.
    Hepatology 55:953-964(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NPC1L1.
  14. "NPC1/NPC2 function as a tag team duo to mobilize cholesterol."
    Subramanian K., Balch W.E.
    Proc. Natl. Acad. Sci. U.S.A. 105:15223-15224(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON FUNCTION.
  15. "Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking."
    Storch J., Xu Z.
    Biochim. Biophys. Acta 1791:671-678(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON FUNCTION.
  16. "Transfer of cholesterol by the NPC team."
    Vance J.E.
    Cell Metab. 12:105-106(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON FUNCTION.
  17. "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.
  18. "Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group."
    Millat G., Chikh K., Naureckiene S., Sleat D.E., Fensom A.H., Higaki K., Elleder M., Lobel P., Vanier M.T.
    Am. J. Hum. Genet. 69:1013-1021(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT NPC2 PRO-67.
  19. "Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2."
    Klunemann H.H., Elleder M., Kaminski W.E., Snow K., Peyser J.M., O'Brien J.F., Munoz D., Schmitz G., Klein H.E., Pendlebury W.W.
    Ann. Neurol. 52:743-749(2002) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT NPC2 MET-39.
  20. "Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1."
    Park W.D., O'Brien J.F., Lundquist P.A., Kraft D.L., Vockley C.W., Karnes P.S., Patterson M.C., Snow K.
    Hum. Mutat. 22:313-325(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS NPC2 MET-30; PHE-47 AND PHE-93.
  21. "Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations."
    Chikh K., Rodriguez C., Vey S., Vanier M.T., Millat G.
    Hum. Mutat. 26:20-28(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT NPC2 ARG-99, CHARACTERIZATION OF VARIANTS NPC2 METH-39; PHE-47; PRO-67; PHE-93 AND ARG-99.
  22. "Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families."
    Millat G., Baielo N., Molinero S., Rodriguez C., Chikh K., Vanier M.T.
    Mol. Genet. Metab. 86:220-232(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANT NPC2 SER-120.

Entry informationi

Entry nameiNPC2_HUMAN
AccessioniPrimary (citable) accession number: P61916
Secondary accession number(s): Q15668, Q29413
Entry historyi
Integrated into UniProtKB/Swiss-Prot: June 7, 2004
Last sequence update: June 7, 2004
Last modified: September 3, 2014
This is version 109 of the entry and version 1 of the sequence. [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

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. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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