NPC2_BOVIN
ID NPC2_BOVIN Reviewed; 149 AA.
AC P79345; Q3T091; Q58DR4;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1997, sequence version 1.
DT 03-AUG-2022, entry version 144.
DE RecName: Full=NPC intracellular cholesterol transporter 2 {ECO:0000250|UniProtKB:P61916};
DE AltName: Full=EPV20 {ECO:0000303|PubMed:9030770};
DE AltName: Full=Epididymal secretory protein E1;
DE AltName: Full=Niemann Pick type C2 protein homolog;
DE Flags: Precursor;
GN Name=NPC2 {ECO:0000250|UniProtKB:P61916};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE, AND DISULFIDE BONDS.
RC TISSUE=Mammary gland;
RX PubMed=9030770; DOI=10.1111/j.1432-1033.1997.0437a.x;
RA Larsen L.B., Ravn P., Boisen A., Berglund L., Petersen T.E.;
RT "Primary structure of EPV20, a secretory glycoprotein containing a
RT previously uncharacterized type of domain.";
RL Eur. J. Biochem. 243:437-441(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=16305752; DOI=10.1186/1471-2164-6-166;
RA Harhay G.P., Sonstegard T.S., Keele J.W., Heaton M.P., Clawson M.L.,
RA Snelling W.M., Wiedmann R.T., Van Tassell C.P., Smith T.P.L.;
RT "Characterization of 954 bovine full-CDS cDNA sequences.";
RL BMC Genomics 6:166-166(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=17552909; DOI=10.1515/bc.2007.063;
RA Babalola J.O., Wendeler M., Breiden B., Arenz C., Schwarzmann G.,
RA Locatelli-Hoops S., Sandhoff K.;
RT "Development of an assay for the intermembrane transfer of cholesterol by
RT Niemann-Pick C2 protein.";
RL Biol. Chem. 388:617-626(2007).
RN [5]
RP FUNCTION.
RX PubMed=18823126; DOI=10.1021/bi801328u;
RA Xu Z., Farver W., Kodukula S., Storch J.;
RT "Regulation of sterol transport between membranes and NPC2.";
RL Biochemistry 47:11134-11143(2008).
RN [6]
RP INTERACTION WITH NPC1.
RX PubMed=22065762; DOI=10.1073/pnas.1110439108;
RA Deffieu M.S., Pfeffer S.R.;
RT "Niemann-Pick type C 1 function requires lumenal domain residues that
RT mediate cholesterol-dependent NPC2 binding.";
RL Proc. Natl. Acad. Sci. U.S.A. 108:18932-18936(2011).
RN [7]
RP INTERACTION WITH NPC1.
RX PubMed=27551080; DOI=10.1073/pnas.1611956113;
RA Li X., Saha P., Li J., Blobel G., Pfeffer S.R.;
RT "Clues to the mechanism of cholesterol transfer from the structure of NPC1
RT middle lumenal domain bound to NPC2.";
RL Proc. Natl. Acad. Sci. U.S.A. 113:10079-10084(2016).
RN [8]
RP FUNCTION.
RX PubMed=29580834; DOI=10.1016/j.chemphyslip.2018.03.006;
RA Berzina Z., Solanko L.M., Mehadi A.S., Jensen M.L.V., Lund F.W., Modzel M.,
RA Szomek M., Solanko K.A., Dupont A., Nielsen G.K., Heegaard C.W.,
RA Ejsing C.S., Wuestner D.;
RT "Niemann-Pick C2 protein regulates sterol transport between plasma membrane
RT and late endosomes in human fibroblasts.";
RL Chem. Phys. Lipids 213:48-61(2018).
RN [9] {ECO:0007744|PDB:1NEP}
RP X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF 20-149, GLYCOSYLATION AT ASN-58,
RP AND DISULFIDE BONDS.
RX PubMed=12591954; DOI=10.1073/pnas.0437840100;
RA Friedland N., Liou H.L., Lobel P., Stock A.M.;
RT "Structure of a cholesterol-binding protein deficient in Niemann-Pick type
RT C2 disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:2512-2517(2003).
RN [10] {ECO:0007744|PDB:2HKA}
RP X-RAY CRYSTALLOGRAPHY (1.81 ANGSTROMS) OF 20-149 IN COMPLEX WITH
RP CHOLESTEROL SULFATE, FUNCTION, GLYCOSYLATION AT ASN-58, AND DISULFIDE
RP BONDS.
RX PubMed=17573352; DOI=10.1074/jbc.m703848200;
RA Xu S., Benoff B., Liou H.L., Lobel P., Stock A.M.;
RT "Structural basis of sterol binding by NPC2, a lysosomal protein deficient
RT in Niemann-Pick type C2 disease.";
RL J. Biol. Chem. 282:23525-23531(2007).
CC -!- FUNCTION: Intracellular cholesterol transporter which acts in concert
CC with NPC1 and plays an important role in the egress of cholesterol from
CC the lysosomal compartment (PubMed:29580834, PubMed:17552909).
CC Unesterified cholesterol that has been released from LDLs in the lumen
CC of the late endosomes/lysosomes is transferred by NPC2 to the
CC cholesterol-binding pocket in the N-terminal domain of NPC1 (By
CC similarity). May bind and mobilize cholesterol that is associated with
CC membranes (PubMed:18823126). NPC2 binds cholesterol with a 1:1
CC stoichiometry (PubMed:17573352). Can bind a variety of sterols,
CC including lathosterol, desmosterol and the plant sterols stigmasterol
CC and beta-sitosterol (By similarity). The secreted form of NCP2
CC regulates biliary cholesterol secretion via stimulation of ABCG5/ABCG8-
CC mediated cholesterol transport (By similarity).
CC {ECO:0000250|UniProtKB:P61916, ECO:0000250|UniProtKB:Q9Z0J0,
CC ECO:0000269|PubMed:17552909, ECO:0000269|PubMed:17573352,
CC ECO:0000269|PubMed:18823126, ECO:0000269|PubMed:29580834}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=cholesterol(in) = cholesterol(out); Xref=Rhea:RHEA:39747,
CC ChEBI:CHEBI:16113; Evidence={ECO:0000269|PubMed:17552909};
CC -!- SUBUNIT: Interacts with NPC1 (via the second lumenal domain) in a
CC cholestrol-dependent manner (PubMed:22065762, PubMed:27551080).
CC Interacts with NUS1/NgBR, the interaction stabilizes NCP2 and regulates
CC cholesterol trafficking. Interacts with DHDDS. Interacts with NEDD4L
CC (via C2 domain). Interacts with NPC1L1 (By similarity).
CC {ECO:0000250|UniProtKB:P61916, ECO:0000269|PubMed:22065762,
CC ECO:0000269|PubMed:27551080}.
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:P61916}.
CC Endoplasmic reticulum {ECO:0000250|UniProtKB:P61916}. Lysosome
CC {ECO:0000250|UniProtKB:P61916}. Note=Interaction with cell-surface M6PR
CC mediates endocytosis and targeting to lysosomes.
CC {ECO:0000250|UniProtKB:P61916}.
CC -!- TISSUE SPECIFICITY: Expressed in kidney, spleen, liver and mammary
CC gland, but not in testis.
CC -!- DOMAIN: Binds cholesterol in a hydrophobic pocket; there are no
CC hydrogen bonds between the sterol and the protein.
CC {ECO:0000269|PubMed:17573352}.
CC -!- SIMILARITY: Belongs to the NPC2 family. {ECO:0000305}.
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DR EMBL; X85799; CAA59794.1; -; mRNA.
DR EMBL; BT021533; AAX46380.1; -; mRNA.
DR EMBL; BC102504; AAI02505.1; -; mRNA.
DR RefSeq; NP_776343.1; NM_173918.2.
DR PDB; 1NEP; X-ray; 1.70 A; A=20-149.
DR PDB; 2HKA; X-ray; 1.81 A; A/B/C=20-149.
DR PDBsum; 1NEP; -.
DR PDBsum; 2HKA; -.
DR AlphaFoldDB; P79345; -.
DR SMR; P79345; -.
DR STRING; 9913.ENSBTAP00000029271; -.
DR SwissLipids; SLP:000000474; -.
DR iPTMnet; P79345; -.
DR PaxDb; P79345; -.
DR PeptideAtlas; P79345; -.
DR PRIDE; P79345; -.
DR Ensembl; ENSBTAT00000029271; ENSBTAP00000029271; ENSBTAG00000021955.
DR GeneID; 280815; -.
DR KEGG; bta:280815; -.
DR CTD; 10577; -.
DR VEuPathDB; HostDB:ENSBTAG00000021955; -.
DR VGNC; VGNC:32196; NPC2.
DR eggNOG; KOG4063; Eukaryota.
DR GeneTree; ENSGT00390000006223; -.
DR HOGENOM; CLU_109192_1_0_1; -.
DR InParanoid; P79345; -.
DR OMA; NLFCWEI; -.
DR OrthoDB; 1612792at2759; -.
DR TreeFam; TF317963; -.
DR Reactome; R-BTA-6798695; Neutrophil degranulation.
DR Reactome; R-BTA-8964038; LDL clearance.
DR EvolutionaryTrace; P79345; -.
DR Proteomes; UP000009136; Chromosome 10.
DR Bgee; ENSBTAG00000021955; Expressed in caput epididymis and 108 other tissues.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IEA:Ensembl.
DR GO; GO:0005764; C:lysosome; IEA:UniProtKB-SubCell.
DR GO; GO:0015485; F:cholesterol binding; ISS:UniProtKB.
DR GO; GO:0120020; F:cholesterol transfer activity; IEA:Ensembl.
DR GO; GO:0019899; F:enzyme binding; IEA:Ensembl.
DR GO; GO:0032934; F:sterol binding; IBA:GO_Central.
DR GO; GO:0033344; P:cholesterol efflux; ISS:UniProtKB.
DR GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0030301; P:cholesterol transport; ISS:UniProtKB.
DR GO; GO:0032367; P:intracellular cholesterol transport; IDA:UniProtKB.
DR GO; GO:0009615; P:response to virus; IEA:Ensembl.
DR GO; GO:0015918; P:sterol transport; IBA:GO_Central.
DR CDD; cd00916; Npc2_like; 1.
DR InterPro; IPR014756; Ig_E-set.
DR InterPro; IPR003172; ML_dom.
DR InterPro; IPR033916; ML_Npc2-like.
DR InterPro; IPR039670; NPC2-like.
DR PANTHER; PTHR11306; PTHR11306; 1.
DR Pfam; PF02221; E1_DerP2_DerF2; 1.
DR SMART; SM00737; ML; 1.
DR SUPFAM; SSF81296; SSF81296; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Cholesterol metabolism;
KW Direct protein sequencing; Disulfide bond; Endoplasmic reticulum;
KW Glycoprotein; Lipid metabolism; Lipid transport; Lysosome;
KW Reference proteome; Secreted; Signal; Steroid metabolism;
KW Sterol metabolism; Transport.
FT SIGNAL 1..19
FT CHAIN 20..149
FT /note="NPC intracellular cholesterol transporter 2"
FT /id="PRO_0000019852"
FT MOD_RES 116
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9Z0J0"
FT CARBOHYD 58
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:12591954,
FT ECO:0000269|PubMed:17573352, ECO:0007744|PDB:1NEP,
FT ECO:0007744|PDB:2HKA"
FT DISULFID 27..140
FT /evidence="ECO:0000269|PubMed:12591954,
FT ECO:0000269|PubMed:17573352, ECO:0000269|PubMed:9030770,
FT ECO:0007744|PDB:1NEP, ECO:0007744|PDB:2HKA"
FT DISULFID 42..47
FT /evidence="ECO:0000269|PubMed:12591954,
FT ECO:0000269|PubMed:17573352, ECO:0000269|PubMed:9030770,
FT ECO:0007744|PDB:1NEP, ECO:0007744|PDB:2HKA"
FT DISULFID 93..99
FT /evidence="ECO:0000269|PubMed:12591954,
FT ECO:0000269|PubMed:17573352, ECO:0000269|PubMed:9030770,
FT ECO:0007744|PDB:1NEP, ECO:0007744|PDB:2HKA"
FT STRAND 25..27
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 31..41
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 43..50
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 54..65
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 71..78
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 81..84
FT /evidence="ECO:0007829|PDB:1NEP"
FT HELIX 92..94
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 99..101
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 106..114
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 121..131
FT /evidence="ECO:0007829|PDB:1NEP"
FT STRAND 137..148
FT /evidence="ECO:0007829|PDB:1NEP"
SQ SEQUENCE 149 AA; 16640 MW; 91156DC7E805B655 CRC64;
MRFLTVAFLF LALSASALAE PVKFKDCGSW VGVIKEVNVS PCPTQPCKLH RGQSYSVNVT
FTSNTQSQSS KAVVHGIVMG IPVPFPIPES DGCKSGIRCP IEKDKTYNYV NKLPVKNEYP
SIKVVVEWEL TDDKNQRFFC WQIPIEVEA
