Skip Header

You are using a version of Internet Explorer that may not display all features of this website. Please upgrade to a modern browser.
Contribute Send feedback
Read comments (?) or add your own

P61916 (NPC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 105. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Epididymal secretory protein E1
Alternative name(s):
Human epididymis-specific protein 1
Short name=He1
Niemann-Pick disease type C2 protein
Gene names
Name:NPC2
Synonyms:HE1
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length151 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.3 Ref.7 Ref.8

Subunit structure

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. Ref.5 Ref.9 Ref.10 Ref.13

Subcellular location

Secreted. Endoplasmic reticulum. Lysosome Ref.10.

Tissue specificity

Epididymis. Ref.9

Induction

Down-regulated in response to enterovirus 71 (EV71) infection. Ref.6

Involvement in disease

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. Ref.4 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22

Sequence similarities

Belongs to the NPC2 family.

Ontologies

Keywords
   Biological processCholesterol metabolism
Lipid metabolism
Steroid metabolism
Sterol metabolism
   Cellular componentEndoplasmic reticulum
Lysosome
Secreted
   Coding sequence diversityPolymorphism
   DiseaseDisease mutation
Niemann-Pick disease
   DomainSignal
   PTMAcetylation
Disulfide bond
Glycoprotein
   Technical termComplete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcholesterol efflux

Inferred from direct assay PubMed 16141411. Source: BHF-UCL

cholesterol homeostasis

Inferred from direct assay PubMed 12719428. Source: UniProtKB

cholesterol metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

cholesterol transport

Inferred from direct assay Ref.8. Source: UniProtKB

glycolipid transport

Traceable author statement Ref.3. Source: HGNC

intracellular cholesterol transport

Inferred from direct assay Ref.7. Source: UniProtKB

intracellular sterol transport

Inferred from direct assay Ref.3. Source: HGNC

phospholipid transport

Traceable author statement Ref.3. Source: HGNC

regulation of isoprenoid metabolic process

Traceable author statement Ref.5. Source: UniProtKB

response to virus

Inferred from expression pattern Ref.6. Source: UniProtKB

   Cellular_componentendoplasmic reticulum

Inferred from electronic annotation. Source: UniProtKB-SubCell

extracellular region

Inferred from electronic annotation. Source: UniProtKB-SubCell

lysosome

Inferred from direct assay Ref.4. Source: HGNC

   Molecular_functioncholesterol binding

Inferred from direct assay Ref.8. Source: UniProtKB

enzyme binding

Inferred from physical interaction Ref.5. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 1919 Ref.3
Chain20 – 151132Epididymal secretory protein E1
PRO_0000019854

Amino acid modifications

Modified residue1161N6-acetyllysine By similarity
Glycosylation581N-linked (GlcNAc...) Ref.3
Glycosylation1351N-linked (GlcNAc...) Ref.3 Ref.11
Disulfide bond27 ↔ 140 By similarity
Disulfide bond42 ↔ 47 By similarity
Disulfide bond93 ↔ 99 By similarity

Natural variations

Natural variant301V → M in NPC2. Ref.20
Corresponds to variant rs151220873 [ dbSNP | Ensembl ].
VAR_043303
Natural variant391V → M in NPC2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes. Ref.19
VAR_015848
Natural variant471C → 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. Ref.20 Ref.21
VAR_043304
Natural variant671S → 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. Ref.18 Ref.21
Corresponds to variant rs11694 [ dbSNP | Ensembl ].
VAR_015849
Natural variant861P → L.
Corresponds to variant rs4688 [ dbSNP | Ensembl ].
VAR_011899
Natural variant931C → 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. Ref.20 Ref.21
VAR_043305
Natural variant991C → 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. Ref.21
VAR_043306
Natural variant1201P → S in NPC2. Ref.22
VAR_043307

Sequences

Sequence LengthMass (Da)Tools
P61916 [UniParc].

Last modified June 7, 2004. Version 1.
Checksum: B141B611805DC910

FASTA15116,570
        10         20         30         40         50         60 
MRFLAATFLL LALSTAAQAE PVQFKDCGSV DGVIKEVNVS PCPTQPCQLS KGQSYSVNVT 

        70         80         90        100        110        120 
FTSNIQSKSS KAVVHGILMG VPVPFPIPEP DGCKSGINCP IQKDKTYSYL NKLPVKSEYP 

       130        140        150 
SIKLVVEWQL QDDKNQSLFC WEIPVQIVSH L 

« Hide

References

« Hide 'large scale' references
[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]"Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L."
Araki N., Ishigami T., Ushio H., Minegishi S., Umemura M., Miyagi Y., Aoki I., Morinaga H., Tamura K., Toya Y., Uchino K., Umemura S.
Biochem. Biophys. Res. Commun. 388:290-296(2009) [PubMed] [Europe PMC] [Abstract]
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]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X67698 mRNA. Translation: CAA47928.1.
BC002532 mRNA. Translation: AAH02532.1.
PIRI38365.
RefSeqNP_006423.1. NM_006432.3.
UniGeneHs.433222.

3D structure databases

ProteinModelPortalP61916.
SMRP61916. Positions 20-147.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid115828. 12 interactions.
IntActP61916. 1 interaction.
STRING9606.ENSP00000238633.

Protein family/group databases

TCDB2.A.6.6.1. the resistance-nodulation-cell division (rnd) superfamily.

PTM databases

PhosphoSiteP61916.

Polymorphism databases

DMDM48429027.

Proteomic databases

PaxDbP61916.
PeptideAtlasP61916.
PRIDEP61916.

Protocols and materials databases

DNASU10577.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000555619; ENSP00000451112; ENSG00000119655.
GeneID10577.
KEGGhsa:10577.
UCSCuc001xpy.3. human.

Organism-specific databases

CTD10577.
GeneCardsGC14M074943.
HGNCHGNC:14537. NPC2.
HPAHPA000835.
MIM601015. gene.
607625. phenotype.
neXtProtNX_P61916.
Orphanet216986. 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.
PharmGKBPA31700.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG281614.
HOGENOMHOG000007181.
HOVERGENHBG018181.
InParanoidP61916.
KOK13443.
PhylomeDBP61916.
TreeFamTF317963.

Gene expression databases

ArrayExpressP61916.
BgeeP61916.
CleanExHS_NPC2.
GenevestigatorP61916.

Family and domain databases

Gene3D2.60.40.770. 1 hit.
InterProIPR014756. Ig_E-set.
IPR003172. ML_dom.
[Graphical view]
PfamPF02221. E1_DerP2_DerF2. 1 hit.
[Graphical view]
SMARTSM00737. ML. 1 hit.
[Graphical view]
SUPFAMSSF81296. SSF81296. 1 hit.
ProtoNetSearch...

Other

ChiTaRSNPC2. human.
GenomeRNAi10577.
NextBio40145.
PMAP-CutDBP61916.
PROP61916.
SOURCESearch...

Entry information

Entry nameNPC2_HUMAN
AccessionPrimary (citable) accession number: P61916
Secondary accession number(s): Q15668, Q29413
Entry history
Integrated into UniProtKB/Swiss-Prot: June 7, 2004
Last sequence update: June 7, 2004
Last modified: April 16, 2014
This is version 105 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 14

Human chromosome 14: entries, gene names and cross-references to MIM