Nicastrin
Also known as: KIAA0253, NCSTN
Function
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). 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.
Classification
- Family (Pfam)
- PF18266 Ncstrn_small, PF05450 Nicastrin
- InterPro
- Ncstrn_small, Nicastrin
- Functional cluster
- Membrane Channels & Lipid-Anchored Proteins
Experimental structures · PDB · 30
- 2N7Q NMR
- 2N7R NMR
- 4UIS EM 4.40A
- 5A63 EM 3.40A
- 5FN2 EM 4.20A
- 5FN3 EM 4.10A
- 5FN4 EM 4.00A
- 5FN5 EM 4.30A
- 6IDF EM 2.70A
- 6IYC EM 2.60A
- 6LQG EM 3.10A
- 6LR4 EM 3.00A
- … and 18 more
A predicted model is available from AlphaFold.
Gene Ontology · 32
- GO:0035577 azurophil granule membrane
- GO:0005769 early endosome
- GO:0005783 endoplasmic reticulum
- GO:0005789 endoplasmic reticulum membrane
- GO:0010008 endosome membrane
- GO:0070062 extracellular exosome
- GO:0005925 focal adhesion
- GO:0070765 gamma-secretase complex
- GO:0005794 Golgi apparatus
- GO:0000139 Golgi membrane
- GO:0005765 lysosomal membrane
- GO:0042470 melanosome
- GO:0016020 membrane
- GO:0005886 plasma membrane
- GO:0042734 presynaptic membrane
- GO:0042383 sarcolemma
- GO:0008021 synaptic vesicle
- GO:0042500 aspartic endopeptidase activity, intramembrane cleaving
- GO:0051117 ATPase binding
- GO:0061133 endopeptidase activator activity
- GO:0070851 growth factor receptor binding
- GO:0030674 protein-macromolecule adaptor activity
- GO:0042987 amyloid precursor protein catabolic process
- GO:0042982 amyloid precursor protein metabolic process
- GO:0034205 amyloid-beta formation
- GO:0021549 cerebellum development
- GO:0006509 membrane protein ectodomain proteolysis
- GO:0031293 membrane protein intracellular domain proteolysis
- GO:0007220 Notch receptor processing
- GO:0007219 Notch signaling pathway
- GO:0016485 protein processing
- GO:0006508 proteolysis
Disease associations
- acne inversa, familial, 1 MONDO:0007728
Drugs targeting this protein · 7
- AVAGACESTAT inhibitor
- NIROGACESTAT inhibitor
- TARENFLURBIL modulator
- RG-4733 inhibitor
- NIROGACESTAT HYDROBROMIDE inhibitor
- BEGACESTAT inhibitor
- SEMAGACESTAT inhibitor
Related proteins · sequence + function similarity
- Nicastrin 0.99
- Nicastrin 0.99
- Nicastrin 0.79
- BOS complex subunit ncln 0.71
- Nicastrin 0.69
- BOS complex subunit NCLN 0.68
- BOS complex subunit NCLN 0.68
- BOS complex subunit NCLN 0.68
- BOS complex subunit NCLN 0.67
- Nicastrin 0.66
- Transferrin receptor protein 2 0.66
- BOS complex subunit NCLN 0.66
Co-cited proteins · studied together in the literature
- Gamma-secretase subunit PEN-2 8 shared papers
- Gamma-secretase subunit APH-1A 7 shared papers
- Presenilin-1 9 shared papers
- Nicastrin 1 shared papers
- Nicastrin 1 shared papers
- Nicastrin 1 shared papers
- Gamma-secretase subunit APH-1B 1 shared papers
- Neurogenic locus notch homolog protein 1 1 shared papers
- Amyloid-beta precursor protein 1 shared papers
- Transmembrane glycoprotein NMB 1 shared papers
- Calumenin 1 shared papers
- Gamma-glutamyl hydrolase 1 shared papers
Literature · 26 cited papers
- Recognition of the amyloid precursor protein by human gamma-secretase. Science · 2019
- Structural basis of Notch recognition by human gamma-secretase. Nature · 2019
- Structure of the transmembrane domain of human nicastrin-a component of gamma-secretase. Sci. Rep. · 2016
- Sampling the conformational space of the catalytic subunit of human gamma-secretase. Elife · 2015
- An atomic structure of human gamma-secretase. Nature · 2015
- N-terminome analysis of the human mitochondrial proteome. Proteomics · 2015
- Structural basis of human gamma-secretase assembly. Proc. Natl. Acad. Sci. U.S.A. · 2015
- Three-dimensional structure of human gamma-secretase. Nature · 2014
- Two novel mutations of the nicastrin gene in Chinese patients with acne inversa. Br. J. Dermatol. · 2011
- Confirmation by exome sequencing of the pathogenic role of NCSTN mutations in acne inversa (hidradenitis suppurativa). J. Invest. Dermatol. · 2011
- Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
- Gamma-secretase gene mutations in familial acne inversa. Science · 2010
- … and 14 more in the literature graph
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