NICA_MOUSE
ID NICA_MOUSE Reviewed; 708 AA.
AC P57716; E9QLZ6; Q8VE20;
DT 11-JAN-2001, integrated into UniProtKB/Swiss-Prot.
DT 27-JUL-2011, sequence version 3.
DT 03-AUG-2022, entry version 164.
DE RecName: Full=Nicastrin;
DE Flags: Precursor;
GN Name=Ncstn;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10993067; DOI=10.1038/35024009;
RA Yu G., Nishimura M., Arawaka S., Levitan D., Zhang L., Tandon A.,
RA Song Y.-Q., Rogaeva E., Chen F., Kawarai T., Supala A., Levesque L., Yu H.,
RA Yang D.-S., Holmes E., Milman P., Liang Y., Zhang D.M., Xu D.H., Sato C.,
RA Rogaev E., Smith M., Janus C., Zhang Y., Aebersold R., Farrer L.S.,
RA Sorbi S., Bruni A., Fraser P.E., St George-Hyslop P.H.;
RT "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction
RT and betaAPP processing.";
RL Nature 407:48-54(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP DISRUPTION PHENOTYPE, FUNCTION, AND SUBUNIT.
RX PubMed=12716934; DOI=10.1523/jneurosci.23-08-03272.2003;
RA Li T., Ma G., Cai H., Price D.L., Wong P.C.;
RT "Nicastrin is required for assembly of presenilin/gamma-secretase complexes
RT to mediate Notch signaling and for processing and trafficking of beta-
RT amyloid precursor protein in mammals.";
RL J. Neurosci. 23:3272-3277(2003).
RN [5]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-186; ASN-263; ASN-386; ASN-505;
RP ASN-561 AND ASN-611.
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-linked
RT cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
CC -!- FUNCTION: Essential subunit of the gamma-secretase complex, an
CC endoprotease complex that catalyzes the intramembrane cleavage of
CC integral membrane proteins such as Notch receptors and APP (amyloid-
CC beta precursor protein). The gamma-secretase complex plays a role in
CC Notch and Wnt signaling cascades and regulation of downstream processes
CC via its role in processing key regulatory proteins, and by regulating
CC cytosolic CTNNB1 levels. {ECO:0000269|PubMed:12716934}.
CC -!- SUBUNIT: Component of the gamma-secretase complex. The functional
CC gamma-secretase complex is composed of at least four polypeptides: a
CC presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A
CC or APH1B) and PEN2 (PubMed:12716934). Binds to proteolytic processed C-
CC terminal fragments C83 and C99 of the amyloid precursor protein (APP).
CC Interacts with PSEN1 and PSEN2. {ECO:0000250|UniProtKB:Q92542,
CC ECO:0000269|PubMed:12716934}.
CC -!- INTERACTION:
CC P57716; P14211: Calr; NbExp=2; IntAct=EBI-998934, EBI-644340;
CC P57716; Q9DBY1: Syvn1; NbExp=2; IntAct=EBI-998934, EBI-644384;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q92542}; Single-
CC pass type I membrane protein {ECO:0000250|UniProtKB:Q92542}.
CC Cytoplasmic vesicle membrane {ECO:0000250|UniProtKB:Q92542}; Single-
CC pass type I membrane protein {ECO:0000250|UniProtKB:Q92542}. Melanosome
CC {ECO:0000250|UniProtKB:Q92542}. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC {ECO:0000250|UniProtKB:Q92542}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q92542}.
CC -!- DISRUPTION PHENOTYPE: Full embryonic lethality. No embryos survive past
CC 10.d dpc. At 9.5 dpc the embryos display a phenotype similar to that of
CC Notch1-deficient mice, with defects in the development of the caudal
CC part of the embryo and in somite segementation, defective vascular
CC morphogenesis in the yolk sac, and patterning defects in the developing
CC heart and neural tube. Assembly of the gamma-secretase complex and APP
CC processing are disrupted. {ECO:0000269|PubMed:12716934}.
CC -!- SIMILARITY: Belongs to the nicastrin family. {ECO:0000305}.
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DR EMBL; AF240469; AAG11413.1; -; mRNA.
DR EMBL; AC158930; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC019998; AAH19998.1; -; mRNA.
DR CCDS; CCDS15507.1; -.
DR RefSeq; NP_067620.3; NM_021607.3.
DR AlphaFoldDB; P57716; -.
DR SMR; P57716; -.
DR BioGRID; 208543; 52.
DR ComplexPortal; CPX-4234; Gamma-secretase complex, Aph1a-Psen1 variant.
DR ComplexPortal; CPX-4235; Gamma-secretase complex, Aph1b-Psen1 variant.
DR ComplexPortal; CPX-4236; Gamma-secretase complex, Aph1a-Psen2 variant.
DR ComplexPortal; CPX-4237; Gamma-secretase complex, Aph1b-Psen2 variant.
DR CORUM; P57716; -.
DR DIP; DIP-36334N; -.
DR IntAct; P57716; 46.
DR MINT; P57716; -.
DR STRING; 10090.ENSMUSP00000003550; -.
DR TCDB; 4.G.1.1.1; the Gama-secretase (Gama-secretase) family.
DR GlyConnect; 2562; 8 N-Linked glycans (7 sites).
DR GlyGen; P57716; 16 sites, 8 N-linked glycans (7 sites).
DR iPTMnet; P57716; -.
DR PhosphoSitePlus; P57716; -.
DR SwissPalm; P57716; -.
DR EPD; P57716; -.
DR jPOST; P57716; -.
DR MaxQB; P57716; -.
DR PaxDb; P57716; -.
DR PeptideAtlas; P57716; -.
DR PRIDE; P57716; -.
DR ProteomicsDB; 287425; -.
DR Antibodypedia; 20490; 543 antibodies from 44 providers.
DR DNASU; 59287; -.
DR Ensembl; ENSMUST00000003550; ENSMUSP00000003550; ENSMUSG00000003458.
DR GeneID; 59287; -.
DR KEGG; mmu:59287; -.
DR UCSC; uc007dpk.2; mouse.
DR CTD; 23385; -.
DR MGI; MGI:1891700; Ncstn.
DR VEuPathDB; HostDB:ENSMUSG00000003458; -.
DR eggNOG; KOG2657; Eukaryota.
DR GeneTree; ENSGT00390000014633; -.
DR HOGENOM; CLU_024257_0_0_1; -.
DR InParanoid; P57716; -.
DR OMA; CMRRNSI; -.
DR OrthoDB; 777987at2759; -.
DR PhylomeDB; P57716; -.
DR TreeFam; TF317086; -.
DR Reactome; R-MMU-1251985; Nuclear signaling by ERBB4.
DR Reactome; R-MMU-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-MMU-205043; NRIF signals cell death from the nucleus.
DR Reactome; R-MMU-3928665; EPH-ephrin mediated repulsion of cells.
DR Reactome; R-MMU-6798695; Neutrophil degranulation.
DR Reactome; R-MMU-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-MMU-9017802; Noncanonical activation of NOTCH3.
DR BioGRID-ORCS; 59287; 9 hits in 74 CRISPR screens.
DR ChiTaRS; Ncstn; mouse.
DR PRO; PR:P57716; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; P57716; protein.
DR Bgee; ENSMUSG00000003458; Expressed in spermatocyte and 204 other tissues.
DR ExpressionAtlas; P57716; baseline and differential.
DR Genevisible; P57716; MM.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005769; C:early endosome; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:MGI.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IC:ComplexPortal.
DR GO; GO:0070765; C:gamma-secretase complex; IDA:MGI.
DR GO; GO:0005794; C:Golgi apparatus; IDA:MGI.
DR GO; GO:0000139; C:Golgi membrane; IC:ComplexPortal.
DR GO; GO:0016021; C:integral component of membrane; ISS:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0099056; C:integral component of presynaptic membrane; ISO:MGI.
DR GO; GO:0005765; C:lysosomal membrane; ISO:MGI.
DR GO; GO:0005764; C:lysosome; IDA:MGI.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0005739; C:mitochondrion; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR GO; GO:0032991; C:protein-containing complex; IDA:MGI.
DR GO; GO:0042383; C:sarcolemma; ISO:MGI.
DR GO; GO:0045202; C:synapse; ISO:MGI.
DR GO; GO:0097060; C:synaptic membrane; ISO:MGI.
DR GO; GO:0008021; C:synaptic vesicle; IDA:MGI.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IGI:MGI.
DR GO; GO:0051117; F:ATPase binding; ISO:MGI.
DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI.
DR GO; GO:0070851; F:growth factor receptor binding; ISO:MGI.
DR GO; GO:0008233; F:peptidase activity; ISO:MGI.
DR GO; GO:0030674; F:protein-macromolecule adaptor activity; ISO:MGI.
DR GO; GO:0030534; P:adult behavior; IMP:MGI.
DR GO; GO:0042983; P:amyloid precursor protein biosynthetic process; IMP:MGI.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; ISO:MGI.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IMP:MGI.
DR GO; GO:0034205; P:amyloid-beta formation; IGI:MGI.
DR GO; GO:0050435; P:amyloid-beta metabolic process; IMP:MGI.
DR GO; GO:0071277; P:cellular response to calcium ion; IMP:MGI.
DR GO; GO:0022010; P:central nervous system myelination; IMP:MGI.
DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl.
DR GO; GO:0007212; P:dopamine receptor signaling pathway; IMP:MGI.
DR GO; GO:0050673; P:epithelial cell proliferation; IMP:MGI.
DR GO; GO:0007215; P:glutamate receptor signaling pathway; IMP:MGI.
DR GO; GO:0007611; P:learning or memory; IMP:MGI.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; ISS:UniProtKB.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; ISO:MGI.
DR GO; GO:0002262; P:myeloid cell homeostasis; IMP:MGI.
DR GO; GO:0051402; P:neuron apoptotic process; IMP:MGI.
DR GO; GO:0070997; P:neuron death; IMP:MGI.
DR GO; GO:0007220; P:Notch receptor processing; ISO:MGI.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:0042986; P:positive regulation of amyloid precursor protein biosynthetic process; IMP:MGI.
DR GO; GO:0043085; P:positive regulation of catalytic activity; ISS:UniProtKB.
DR GO; GO:0010950; P:positive regulation of endopeptidase activity; ISO:MGI.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
DR GO; GO:1900271; P:regulation of long-term synaptic potentiation; IMP:MGI.
DR GO; GO:1990926; P:short-term synaptic potentiation; IMP:MGI.
DR GO; GO:0042098; P:T cell proliferation; IMP:MGI.
DR InterPro; IPR041084; Ncstrn_small.
DR InterPro; IPR008710; Nicastrin.
DR PANTHER; PTHR21092; PTHR21092; 1.
DR Pfam; PF18266; Ncstrn_small; 1.
PE 1: Evidence at protein level;
KW Cytoplasmic vesicle; Disulfide bond; Glycoprotein; Membrane;
KW Notch signaling pathway; Reference proteome; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1..27
FT /evidence="ECO:0000255"
FT CHAIN 28..708
FT /note="Nicastrin"
FT /id="PRO_0000019682"
FT TOPO_DOM 28..668
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT TRANSMEM 669..689
FT /note="Helical"
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT TOPO_DOM 690..708
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT CARBOHYD 44
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 54
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 128
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 186
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 203
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 263
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 386
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 434
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 463
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 505
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 529
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 561
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT CARBOHYD 572
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 579
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 593
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 611
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:19349973"
FT DISULFID 49..61
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT DISULFID 139..158
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT DISULFID 194..212
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT DISULFID 229..247
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT DISULFID 585..619
FT /evidence="ECO:0000250|UniProtKB:Q92542"
FT CONFLICT 527
FT /note="R -> K (in Ref. 1; AAG11413 and 3; AAH19998)"
FT /evidence="ECO:0000305"
FT CONFLICT 666
FT /note="E -> K (in Ref. 1; AAG11413)"
FT /evidence="ECO:0000305"
FT CONFLICT 678..680
FT /note="TLV -> ILI (in Ref. 1; AAG11413 and 3; AAH19998)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 708 AA; 78492 MW; 32B57BB478FEB0AC CRC64;
MATTRGGSGP DPGSRGLLLL SFSVVLAGLC GGNSVERKIY IPLNKTAPCV RLLNATHQIG
CQSSISGDTG VIHVVEKEED LKWVLTDGPN PPYMVLLEGK LFTRDVMEKL KGTTSRIAGL
AVTLAKPNST SSFSPSVQCP NDGFGIYSNS YGPEFAHCKK TLWNELGNGL AYEDFSFPIF
LLEDENETKV IKQCYQDHNL GQNGSAPSFP LCAMQLFSHM HAVISTATCM RRSFIQSTFS
INPEIVCDPL SDYNVWSMLK PINTSVGLEP DVRVVVAATR LDSRSFFWNV APGAESAVAS
FVTQLAAAEA LHKAPDVTTL SRNVMFVFFQ GETFDYIGSS RMVYDMENGK FPVRLENIDS
FVELGQVALR TSLDLWMHTD PMSQKNESVK NQVEDLLATL EKSGAGVPEV VLRRLAQSQA
LPPSSLQRFL RARNISGVVL ADHSGSFHNR YYQSIYDTAE NINVTYPEWQ SPEEDLNFVT
DTAKALANVA TVLARALYEL AGGTNFSSSI QADPQTVTRL LYGFLVRANN SWFQSILKHD
LRSYLDDRPL QHYIAVSSPT NTTYVVQYAL ANLTGKATNL TREQCQDPSK VPNESKDLYE
YSWVQGPWNS NRTERLPQCV RSTVRLARAL SPAFELSQWS STEYSTWAES RWKDIQARIF
LIASKELEFI TLIVGFSTLV FSLIVTYCIN AKADVLFVAP REPGAVSY
