P61916 (NPC2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	151 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 (NPDC2) [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 process	Cholesterol metabolism Lipid metabolism Steroid metabolism Sterol metabolism
Cellular component	Endoplasmic reticulum Lysosome Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation Niemann-Pick disease
Domain	Signal
PTM	Disulfide bond Glycoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	cholesterol 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 glycolipid transport Traceable author statement Ref.3. Source: HGNC intracellular cholesterol transport Inferred from direct assay Ref.7. Source: UniProtKB 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_component	endoplasmic 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_function	cholesterol binding Inferred from direct assay Ref.8. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 19	19	Ref.3
	Chain	20 – 151	132	Epididymal secretory protein E1		PRO_0000019854
Amino acid modifications
	Glycosylation	58	1	N-linked (GlcNAc...) Ref.3
	Glycosylation	135	1	N-linked (GlcNAc...) Ref.3 Ref.11
	Disulfide bond	27 ↔ 140		By similarity
	Disulfide bond	42 ↔ 47		By similarity
	Disulfide bond	93 ↔ 99		By similarity
Natural variations
	Natural variant	30	1	V → M in NPDC2. Ref.20		VAR_043303
	Natural variant	39	1	V → M in NPDC2; results in the synthesis of functional recombinant proteins correctly targeted to lysosomes. Ref.19		VAR_015848
	Natural variant	47	1	C → F in NPDC2; 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 variant	67	1	S → P in NPDC2; 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 variant	86	1	P → L. Corresponds to variant rs4688 [ dbSNP | Ensembl ].		VAR_011899
	Natural variant	93	1	C → F in NPDC2; 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 variant	99	1	C → R in NPDC2; 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 variant	120	1	P → S in NPDC2. Ref.22		VAR_043307

Sequences

	Sequence		Length	Mass (Da)
	P61916 [UniParc]. Last modified June 7, 2004. Version 1. Checksum: B141B611805DC910	FASTA	151	16,570
	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

References

	« Hide 'large scale' referencesShow '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 NPDC2.
[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, 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, MASS SPECTROMETRY. 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 NPDC2 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 NPDC2 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 NPDC2 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 NPDC2 ARG-99, CHARACTERIZATION OF VARIANTS NPDC2 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 NPDC2 SER-120.
+	Additional computationally mapped references.

Web resources

Niemann-Pick type C disease gene variation database

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	X67698 mRNA. Translation: CAA47928.1. BC002532 mRNA. Translation: AAH02532.1.
IPI	IPI00940960.
PIR	I38365.
RefSeq	NP_006423.1. NM_006432.3.
UniGene	Hs.433222.
3D structure databases
ProteinModelPortal	P61916.
ModBase	Search...
Protein-protein interaction databases
IntAct	P61916. 1 interaction.
STRING	9606.ENSP00000238633.
Protein family/group databases
TCDB	2.A.6.6.1. resistance-nodulation-cell division (RND) superfamily.
PTM databases
PhosphoSite	P61916.
Polymorphism databases
DMDM	48429027.
Proteomic databases
PaxDb	P61916.
PeptideAtlas	P61916.
PRIDE	P61916.
Protocols and materials databases
DNASU	10577.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000555619; ENSP00000451112; ENSG00000119655.
GeneID	10577.
KEGG	hsa:10577.
UCSC	uc001xpy.3. human.
Organism-specific databases
CTD	10577.
GeneCards	GC14M074943.
HGNC	HGNC:14537. NPC2.
HPA	HPA000835.
MIM	601015. gene. 607625. phenotype.
neXtProt	NX_P61916.
Orphanet	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.
PharmGKB	PA31700.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG281614.
HOGENOM	HOG000007181.
HOVERGEN	HBG018181.
InParanoid	P61916.
KO	K13443.
OrthoDB	EOG4BZN42.
PhylomeDB	P61916.
Gene expression databases
ArrayExpress	P61916.
Bgee	P61916.
CleanEx	HS_NPC2.
Genevestigator	P61916.
GermOnline	ENSG00000119655. Homo sapiens.
Family and domain databases
Gene3D	2.60.40.770. 1 hit.
InterPro	IPR014756. Ig_E-set. IPR003172. MD-2_lipid-recog_dom. [Graphical view]
Pfam	PF02221. E1_DerP2_DerF2. 1 hit. [Graphical view]
SMART	SM00737. ML. 1 hit. [Graphical view]
SUPFAM	SSF81296. Ig_E-set. 1 hit.
ProtoNet	Search...
Other
ChiTaRS	NPC2. human.
GenomeRNAi	10577.
NextBio	40145.
PMAP-CutDB	P61916.
SOURCE	Search...

Entry information

Entry name

NPC2_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 95 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.