Nicastrin

Nicastrin
Identifiers
Symbols	NCSTN; APH2; KIAA0253
External IDs	OMIM: 605254 MGI: 1891700 HomoloGene: 41029 GeneCards: NCSTN Gene
Gene Ontology Molecular function • protein binding • peptidase activity Cellular component • membrane fraction • lysosomal membrane • endoplasmic reticulum • endoplasmic reticulum • Golgi apparatus • Golgi apparatus • plasma membrane • plasma membrane • integral to plasma membrane • integral to plasma membrane • integral to membrane • melanosome Biological process • proteolysis • membrane protein ectodomain proteolysis • membrane protein ectodomain proteolysis • apoptosis • Notch signaling pathway • Notch receptor processing • induction of apoptosis by extracellular signals • protein processing • protein processing • membrane protein intracellular domain proteolysis • amyloid precursor protein catabolic process • positive regulation of catalytic activity • positive regulation of catalytic activity • nerve growth factor receptor signaling pathway Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	23385	59287
Ensembl	ENSG00000162736	ENSMUSG00000003458
UniProt	Q92542	Q3T9E5
RefSeq (mRNA)	NM_015331.2	NM_021607.3
RefSeq (protein)	NP_056146.1	NP_067620.3
Location (UCSC)	Chr 1: 160.31 – 160.33 Mb	Chr 1: 174 – 174.01 Mb
PubMed search	[1]	[2]

Nicastrin, also known as NCSTN, is a protein which in humans is encoded by the NCSTN gene.^[1][2][3]

Nicastrin (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein (APP) to the short Alzheimer's disease-associated peptide amyloid beta. The other proteins in the complex are presenilin, which is the catalytically active component of the complex, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2).^[4] Nicastrin itself is not catalytically active, but instead promotes the maturation and proper trafficking of the other proteins in the complex, all of which undergo significant post-translational modification before becoming active in the cell.^[5] Nicastrin has also been identified as a regulator of neprilysin, an enzyme involved in the degradation of amyloid beta fragment.^[6]

History

The protein was named after the Italian village Nicastro, reflecting the fact that Alzheimer's disease was described in 1963 after studying descendants of an extended family originating in the village of Nicastro that had Familial Alzheimer's Disease (FAD).^[7]

Interactions

Nicastrin has been shown to interact with PSEN1^{[8][9][10][11][3]} and PSEN2.^[11][3]

References

1. ^ "Entrez Gene: NCSTN nicastrin". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23385. 
2. ^ Nagase T, Seki N, Ishikawa K, Ohira M, Kawarabayasi Y, Ohara O, Tanaka A, Kotani H, Miyajima N, Nomura N (October 1996). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain". DNA Res. 3 (5): 321–9, 341–54. doi:10.1093/dnares/3.5.321. PMID 9039502. http://dnaresearch.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=9039502. 
3. ^ ^{a b c} Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (September 2000). "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing". Nature 407 (6800): 48–54. doi:10.1038/35024009. PMID 10993067. 
4. ^ Kaether C, Haass C, Steiner H (2006). "Assembly, trafficking and function of gamma-secretase". Neurodegener Dis 3 (4–5): 275–83. doi:10.1159/000095267. PMID 17047368. 
5. ^ Zhang YW, Luo WJ, Wang H, Lin P, Vetrivel KS, Liao F, Li F, Wong PC, Farquhar MG, Thinakaran G, Xu H (April 2005). "Nicastrin is critical for stability and trafficking but not association of other presenilin/gamma-secretase components". J. Biol. Chem. 280 (17): 17020–6. doi:10.1074/jbc.M409467200. PMC 1201533. PMID 15711015. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1201533. 
6. ^ Pardossi-Piquard R, Dunys J, Yu G, St George-Hyslop P, Alves da Costa C, Checler F (May 2006). "Neprilysin activity and expression are controlled by nicastrin". J. Neurochem. 97 (4): 1052–6. doi:10.1111/j.1471-4159.2006.03822.x. PMID 16606360. 
7. ^ Feldman RG, Chandler KA, Levy LL, Gaser GH (October 1963). "Familial Alzheimer's Disease". Neurology 13: 811–24. PMID 14066996. 
8. ^ Haffner, Christof; Frauli Mélanie, Topp Stephanie, Irmler Martin, Hofmann Kay, Regula Jörg T, Bally-Cuif Laure, Haass Christian (Aug. 2004). "Nicalin and its binding partner Nomo are novel Nodal signaling antagonists". EMBO J. (England) 23 (15): 3041–50. doi:10.1038/sj.emboj.7600307. ISSN 0261-4189. PMC 514924. PMID 15257293. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=514924. 
9. ^ Baulac, Stephanie; LaVoie Matthew J, Kimberly W Taylor, Strahle Jennifer, Wolfe Michael S, Selkoe Dennis J, Xia Weiming (Nov. 2003). "Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates". Neurobiol. Dis. (United States) 14 (2): 194–204. doi:10.1016/S0969-9961(03)00123-2. ISSN 0969-9961. PMID 14572442. 
10. ^ Gu, Yongjun; Chen Fusheng, Sanjo Nobuo, Kawarai Toshitaka, Hasegawa Hiroshi, Duthie Monica, Li Wenping, Ruan Xueying, Luthra Anchla, Mount Howard T J, Tandon Anurag, Fraser Paul E, St George-Hyslop Peter (Feb. 2003). "APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes". J. Biol. Chem. (United States) 278 (9): 7374–80. doi:10.1074/jbc.M209499200. ISSN 0021-9258. PMID 12471034. 
11. ^ ^{a b} Lee, Sheu-Fen; Shah Sanjiv, Li Hongqiao, Yu Cong, Han Weiping, Yu Gang (Nov. 2002). "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch". J. Biol. Chem. (United States) 277 (47): 45013–9. doi:10.1074/jbc.M208164200. ISSN 0021-9258. PMID 12297508. 

Further reading

• Nagase T, Seki N, Ishikawa K, et al. (1997). "Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain". DNA Res. 3 (5): 321–9, 341–54. doi:10.1093/dnares/3.5.321. PMID 9039502. 
• Yu G, Nishimura M, Arawaka S, et al. (2000). "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing". Nature 407 (6800): 48–54. doi:10.1038/35024009. PMID 10993067. 
• Fagan R, Swindells M, Overington J, Weir M (2001). "Nicastrin, a presenilin-interacting protein, contains an aminopeptidase/transferrin receptor superfamily domain". Trends Biochem. Sci. 26 (4): 213–4. doi:10.1016/S0968-0004(01)01789-3. PMID 11295540. 
• Satoh J, Kuroda Y (2001). "Nicastrin, a key regulator of presenilin function, is expressed constitutively in human neural cell lines". Neuropathology : official journal of the Japanese Society of Neuropathology 21 (2): 115–22. PMID 11396676. 
• Chen F, Yu G, Arawaka S, et al. (2001). "Nicastrin binds to membrane-tethered Notch". Nat. Cell Biol. 3 (8): 751–4. doi:10.1038/35087069. PMID 11483961. 
• Fergani A, Yu G, St George-Hyslop P, Checler F (2002). "Wild-type and mutated nicastrins do not display aminopeptidase M- and B-like activities". Biochem. Biophys. Res. Commun. 289 (3): 678–80. doi:10.1006/bbrc.2001.6030. PMID 11726200. 
• Leem JY, Vijayan S, Han P, et al. (2002). "Presenilin 1 is required for maturation and cell surface accumulation of nicastrin". J. Biol. Chem. 277 (21): 19236–40. doi:10.1074/jbc.C200148200. PMID 11943765. 
• Dermaut B, Theuns J, Sleegers K, et al. (2002). "The gene encoding nicastrin, a major gamma-secretase component, modifies risk for familial early-onset Alzheimer disease in a Dutch population-based sample". Am. J. Hum. Genet. 70 (6): 1568–74. doi:10.1086/340732. PMC 379144. PMID 11992262. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=379144. 
• Li B, Cong F, Tan CP, et al. (2002). "Aph2, a protein with a zf-DHHC motif, interacts with c-Abl and has pro-apoptotic activity". J. Biol. Chem. 277 (32): 28870–6. doi:10.1074/jbc.M202388200. PMID 12021275. 
• Yang DS, Tandon A, Chen F, et al. (2002). "Mature glycosylation and trafficking of nicastrin modulate its binding to presenilins". J. Biol. Chem. 277 (31): 28135–42. doi:10.1074/jbc.M110871200. PMID 12032140. 
• Tomita T, Katayama R, Takikawa R, Iwatsubo T (2002). "Complex N-glycosylated form of nicastrin is stabilized and selectively bound to presenilin fragments". FEBS Lett. 520 (1–3): 117–21. doi:10.1016/S0014-5793(02)02802-8. PMID 12044882. 
• Edbauer D, Winkler E, Haass C, Steiner H (2002). "Presenilin and nicastrin regulate each other and determine amyloid beta-peptide production via complex formation". Proc. Natl. Acad. Sci. U.S.A. 99 (13): 8666–71. doi:10.1073/pnas.132277899. PMC 124353. PMID 12048259. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=124353. 
• Hattori C, Asai M, Oma Y, et al. (2002). "BACE1 interacts with nicastrin". Biochem. Biophys. Res. Commun. 293 (4): 1228–32. doi:10.1016/S0006-291X(02)00351-0. PMID 12054507. 
• Kimberly WT, LaVoie MJ, Ostaszewski BL, et al. (2002). "Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation". J. Biol. Chem. 277 (38): 35113–7. doi:10.1074/jbc.M204446200. PMID 12130643. 
• Steiner H, Winkler E, Edbauer D, et al. (2002). "PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin". J. Biol. Chem. 277 (42): 39062–5. doi:10.1074/jbc.C200469200. PMID 12198112. 
• Lee SF, Shah S, Li H, et al. (2003). "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch". J. Biol. Chem. 277 (47): 45013–9. doi:10.1074/jbc.M208164200. PMID 12297508. 
• Gu Y, Chen F, Sanjo N, et al. (2003). "APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes". J. Biol. Chem. 278 (9): 7374–80. doi:10.1074/jbc.M209499200. PMID 12471034. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Siman R, Velji J (2003). "Localization of presenilin-nicastrin complexes and gamma-secretase activity to the trans-Golgi network". J. Neurochem. 84 (5): 1143–53. doi:10.1046/j.1471-4159.2003.01616.x. PMID 12603837. 
• Basrur V, Yang F, Kushimoto T, et al. (2003). "Proteomic analysis of early melanosomes: identification of novel melanosomal proteins". J. Proteome Res. 2 (1): 69–79. doi:10.1021/pr025562r. PMID 12643545. 

External links

• MeSH nicastrin+protein