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Protein

Nicastrin

Gene

NCSTN

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.4 Publications

GO - Molecular functioni

  • endopeptidase activity Source: GO_Central

GO - Biological processi

Keywordsi

Biological processNotch signaling pathway

Enzyme and pathway databases

ReactomeiR-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-1474228 Degradation of the extracellular matrix
R-HSA-193692 Regulated proteolysis of p75NTR
R-HSA-205043 NRIF signals cell death from the nucleus
R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
R-HSA-6798695 Neutrophil degranulation
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802 Noncanonical activation of NOTCH3
SignaLinkiQ92542
SIGNORiQ92542

Names & Taxonomyi

Protein namesi
Recommended name:
Nicastrin
Gene namesi
Name:NCSTN
Synonyms:KIAA0253
ORF Names:UNQ1874/PRO4317
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000162736.15
HGNCiHGNC:17091 NCSTN
MIMi605254 gene
neXtProtiNX_Q92542

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini34 – 669Extracellular2 PublicationsAdd BLAST636
Transmembranei670 – 690Helical2 PublicationsAdd BLAST21
Topological domaini691 – 709Cytoplasmic2 PublicationsAdd BLAST19

Keywords - Cellular componenti

Cytoplasmic vesicle, Membrane

Pathology & Biotechi

Involvement in diseasei

Acne inversa, familial, 1 (ACNINV1)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.
See also OMIM:142690
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_067756211P → R in ACNINV1. 1 Publication1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi336 – 337DY → AA: Increases production of amyloid-beta (beta-APP40 and beta-APP42) in APP processing. 1 Publication2

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi23385
MalaCardsiNCSTN
MIMi142690 phenotype
OpenTargetsiENSG00000162736
Orphaneti387 NON RARE IN EUROPE: Hidradenitis suppurativa
PharmGKBiPA142671271

Chemistry databases

ChEMBLiCHEMBL3418

Polymorphism and mutation databases

BioMutaiNCSTN
DMDMi12231037

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 33Sequence analysisAdd BLAST33
ChainiPRO_000001968134 – 709NicastrinAdd BLAST676

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi45N-linked (GlcNAc...) asparagineCombined sources2 Publications1
Disulfide bondi50 ↔ 62Combined sources2 Publications2 Publications
Glycosylationi55N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Disulfide bondi140 ↔ 159Combined sources2 Publications
Glycosylationi187N-linked (GlcNAc...) asparagineCombined sources2 Publications1
Disulfide bondi195 ↔ 213Combined sources1 Publication2 Publications
Glycosylationi200N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi204N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi230 ↔ 248Combined sources1 Publication2 Publications
Glycosylationi264N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi387N-linked (GlcNAc...) asparagineCombined sources3 Publications1
Glycosylationi417N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi435N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi464N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi506N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi530N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi562N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi573N-linked (GlcNAc...) asparagineSequence analysisCombined sources1 Publication1
Glycosylationi580N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi586 ↔ 620Combined sources2 Publications
Glycosylationi612N-linked (GlcNAc...) asparagine1 Publication1

Post-translational modificationi

N-glycosylated.3 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein

Proteomic databases

EPDiQ92542
MaxQBiQ92542
PaxDbiQ92542
PeptideAtlasiQ92542
PRIDEiQ92542
ProteomicsDBi75302
75303 [Q92542-2]
TopDownProteomicsiQ92542-2 [Q92542-2]

PTM databases

GlyConnecti1567
iPTMnetiQ92542
PhosphoSitePlusiQ92542
SwissPalmiQ92542

Expressioni

Tissue specificityi

Detected in brain (at protein level) (PubMed:10993067). Widely expressed (PubMed:11396676).2 Publications

Inductioni

Constitutively expressed in neural cells.1 Publication

Gene expression databases

BgeeiENSG00000162736 Expressed in 224 organ(s), highest expression level in placenta
CleanExiHS_NCSTN
ExpressionAtlasiQ92542 baseline and differential
GenevisibleiQ92542 HS

Organism-specific databases

HPAiCAB021982
HPA054846
HPA070642

Interactioni

Subunit structurei

Component of the gamma-secretase complex (PubMed:10993067). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:25918421). Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (PubMed:10993067). Interacts with PSEN1 and PSEN2 (PubMed:10993067).6 Publications

Binary interactionsi

Protein-protein interaction databases

BioGridi116961, 136 interactors
CORUMiQ92542
DIPiDIP-36336N
IntActiQ92542, 67 interactors
MINTiQ92542
STRINGi9606.ENSP00000294785

Chemistry databases

BindingDBiQ92542

Structurei

Secondary structure

1709
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ92542
SMRiQ92542
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Sequence similaritiesi

Belongs to the nicastrin family.Curated

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2657 Eukaryota
ENOG410XT6X LUCA
GeneTreeiENSGT00390000014633
HOGENOMiHOG000044212
HOVERGENiHBG006497
InParanoidiQ92542
KOiK06171
OMAiGPLNSNE
OrthoDBiEOG091G03DV
PhylomeDBiQ92542
TreeFamiTF317086

Family and domain databases

InterProiView protein in InterPro
IPR008710 Nicastrin
PANTHERiPTHR21092 PTHR21092, 1 hit
PfamiView protein in Pfam
PF05450 Nicastrin, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 9 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: Q92542-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide
        10         20         30         40         50
MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC
60 70 80 90 100
VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDGP NPPYMVLLES
110 120 130 140 150
KHFTRDLMEK LKGRTSRIAG LAVSLTKPSP ASGFSPSVQC PNDGFGVYSN
160 170 180 190 200
SYGPEFAHCR EIQWNSLGNG LAYEDFSFPI FLLEDENETK VIKQCYQDHN
210 220 230 240 250
LSQNGSAPTF PLCAMQLFSH MHAVISTATC MRRSSIQSTF SINPEIVCDP
260 270 280 290 300
LSDYNVWSML KPINTTGTLK PDDRVVVAAT RLDSRSFFWN VAPGAESAVA
310 320 330 340 350
SFVTQLAAAE ALQKAPDVTT LPRNVMFVFF QGETFDYIGS SRMVYDMEKG
360 370 380 390 400
KFPVQLENVD SFVELGQVAL RTSLELWMHT DPVSQKNESV RNQVEDLLAT
410 420 430 440 450
LEKSGAGVPA VILRRPNQSQ PLPPSSLQRF LRARNISGVV LADHSGAFHN
460 470 480 490 500
KYYQSIYDTA ENINVSYPEW LSPEEDLNFV TDTAKALADV ATVLGRALYE
510 520 530 540 550
LAGGTNFSDT VQADPQTVTR LLYGFLIKAN NSWFQSILRQ DLRSYLGDGP
560 570 580 590 600
LQHYIAVSSP TNTTYVVQYA LANLTGTVVN LTREQCQDPS KVPSENKDLY
610 620 630 640 650
EYSWVQGPLH SNETDRLPRC VRSTARLARA LSPAFELSQW SSTEYSTWTE
660 670 680 690 700
SRWKDIRARI FLIASKELEL ITLTVGFGIL IFSLIVTYCI NAKADVLFIA

PREPGAVSY
Length:709
Mass (Da):78,411
Last modified:January 11, 2001 - v2
Checksum:iC8C0EAEAD89E976A
GO
Isoform 2 (identifier: Q92542-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-20: Missing.
     21-29: LSFCVLLAG → MDFNLILES

Note: No experimental confirmation available.
Show »
Length:689
Mass (Da):76,744
Checksum:i58A8EE3F50F93459
GO

Computationally mapped potential isoform sequencesi

There are 9 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
Q5T209Q5T209_HUMAN
Nicastrin
NCSTN
255Annotation score:
Q5T210Q5T210_HUMAN
Nicastrin
NCSTN
232Annotation score:
Q5T211Q5T211_HUMAN
Nicastrin
NCSTN
134Annotation score:
Q5T205Q5T205_HUMAN
Nicastrin
NCSTN
219Annotation score:
H0Y6T7H0Y6T7_HUMAN
Nicastrin
NCSTN
275Annotation score:
H0Y3Z4H0Y3Z4_HUMAN
Nicastrin
NCSTN
316Annotation score:
A0A2U3TZL9A0A2U3TZL9_HUMAN
Nicastrin
NCSTN
69Annotation score:
A0A2R8YCK1A0A2R8YCK1_HUMAN
Nicastrin
NCSTN
69Annotation score:
A0A2R8YE20A0A2R8YE20_HUMAN
Nicastrin
NCSTN
71Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti657R → H in AAH47621 (PubMed:15489334).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_05027475V → I. Corresponds to variant dbSNP:rs12045198Ensembl.1
Natural variantiVAR_05027577E → D. Corresponds to variant dbSNP:rs35603924Ensembl.1
Natural variantiVAR_067756211P → R in ACNINV1. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0083851 – 20Missing in isoform 2. 1 PublicationAdd BLAST20
Alternative sequenceiVSP_00838621 – 29LSFCVLLAG → MDFNLILES in isoform 2. 1 Publication9

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF240468 mRNA Translation: AAG11412.1
AY359120 mRNA Translation: AAQ89478.1
AK314764 mRNA Translation: BAG37302.1
AL445230 Genomic DNA No translation available.
CH471121 Genomic DNA Translation: EAW52720.1
CH471121 Genomic DNA Translation: EAW52721.1
CH471121 Genomic DNA Translation: EAW52722.1
BC047621 mRNA Translation: AAH47621.1
D87442 mRNA Translation: BAA13383.1
CCDSiCCDS1203.1 [Q92542-1]
RefSeqiNP_001277113.1, NM_001290184.1 [Q92542-2]
NP_001277115.1, NM_001290186.1
NP_056146.1, NM_015331.2 [Q92542-1]
UniGeneiHs.517249

Genome annotation databases

EnsembliENST00000294785; ENSP00000294785; ENSG00000162736 [Q92542-1]
GeneIDi23385
KEGGihsa:23385
UCSCiuc001fvx.4 human [Q92542-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF240468 mRNA Translation: AAG11412.1
AY359120 mRNA Translation: AAQ89478.1
AK314764 mRNA Translation: BAG37302.1
AL445230 Genomic DNA No translation available.
CH471121 Genomic DNA Translation: EAW52720.1
CH471121 Genomic DNA Translation: EAW52721.1
CH471121 Genomic DNA Translation: EAW52722.1
BC047621 mRNA Translation: AAH47621.1
D87442 mRNA Translation: BAA13383.1
CCDSiCCDS1203.1 [Q92542-1]
RefSeqiNP_001277113.1, NM_001290184.1 [Q92542-2]
NP_001277115.1, NM_001290186.1
NP_056146.1, NM_015331.2 [Q92542-1]
UniGeneiHs.517249

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2N7QNMR-A664-709[»]
2N7RNMR-A664-709[»]
4UISelectron microscopy4.40A42-665[»]
5A63electron microscopy3.40A1-709[»]
5FN2electron microscopy4.20A1-709[»]
5FN3electron microscopy4.10A1-709[»]
5FN4electron microscopy4.00A1-709[»]
5FN5electron microscopy4.30A1-709[»]
ProteinModelPortaliQ92542
SMRiQ92542
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi116961, 136 interactors
CORUMiQ92542
DIPiDIP-36336N
IntActiQ92542, 67 interactors
MINTiQ92542
STRINGi9606.ENSP00000294785

Chemistry databases

BindingDBiQ92542
ChEMBLiCHEMBL3418

PTM databases

GlyConnecti1567
iPTMnetiQ92542
PhosphoSitePlusiQ92542
SwissPalmiQ92542

Polymorphism and mutation databases

BioMutaiNCSTN
DMDMi12231037

Proteomic databases

EPDiQ92542
MaxQBiQ92542
PaxDbiQ92542
PeptideAtlasiQ92542
PRIDEiQ92542
ProteomicsDBi75302
75303 [Q92542-2]
TopDownProteomicsiQ92542-2 [Q92542-2]

Protocols and materials databases

DNASUi23385
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000294785; ENSP00000294785; ENSG00000162736 [Q92542-1]
GeneIDi23385
KEGGihsa:23385
UCSCiuc001fvx.4 human [Q92542-1]

Organism-specific databases

CTDi23385
DisGeNETi23385
EuPathDBiHostDB:ENSG00000162736.15
GeneCardsiNCSTN
HGNCiHGNC:17091 NCSTN
HPAiCAB021982
HPA054846
HPA070642
MalaCardsiNCSTN
MIMi142690 phenotype
605254 gene
neXtProtiNX_Q92542
OpenTargetsiENSG00000162736
Orphaneti387 NON RARE IN EUROPE: Hidradenitis suppurativa
PharmGKBiPA142671271
HUGEiSearch...
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG2657 Eukaryota
ENOG410XT6X LUCA
GeneTreeiENSGT00390000014633
HOGENOMiHOG000044212
HOVERGENiHBG006497
InParanoidiQ92542
KOiK06171
OMAiGPLNSNE
OrthoDBiEOG091G03DV
PhylomeDBiQ92542
TreeFamiTF317086

Enzyme and pathway databases

ReactomeiR-HSA-1251985 Nuclear signaling by ERBB4
R-HSA-1474228 Degradation of the extracellular matrix
R-HSA-193692 Regulated proteolysis of p75NTR
R-HSA-205043 NRIF signals cell death from the nucleus
R-HSA-2122948 Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606 Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2894862 Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096 NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
R-HSA-6798695 Neutrophil degranulation
R-HSA-9013507 NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-9013700 NOTCH4 Activation and Transmission of Signal to the Nucleus
R-HSA-9017802 Noncanonical activation of NOTCH3
SignaLinkiQ92542
SIGNORiQ92542

Miscellaneous databases

ChiTaRSiNCSTN human
GeneWikiiNicastrin
GenomeRNAii23385
PROiPR:Q92542
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000162736 Expressed in 224 organ(s), highest expression level in placenta
CleanExiHS_NCSTN
ExpressionAtlasiQ92542 baseline and differential
GenevisibleiQ92542 HS

Family and domain databases

InterProiView protein in InterPro
IPR008710 Nicastrin
PANTHERiPTHR21092 PTHR21092, 1 hit
PfamiView protein in Pfam
PF05450 Nicastrin, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiNICA_HUMAN
AccessioniPrimary (citable) accession number: Q92542
Secondary accession number(s): Q5T207, Q5T208, Q86VV5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: July 15, 1998
Last sequence update: January 11, 2001
Last modified: November 7, 2018
This is version 176 of the entry and version 2 of the sequence. See 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

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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