cd03881

M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex

CDD entry
Member databaseCDD
CDD typedomain
Short nameM28_Nicastrin
SetZinc_peptidase_like

Description

Peptidase M28 family, nicastrin subfamily. Nicastrin is a main component of the gamma-secretase complex, which also contains presenilin, Pen-2 and Aph-1. Its extracellular domain sequence resembles aminopeptidases, but certain catalytic residues are not conserved. It is mainly localized to the endoplasmic reticulum and Golgi. It is highly glycosylated (Mr 120 kDa) and is essential for substrate recognition of the N-terminus of gamma-secretase substrates derived from APP and Notch. Nicastrin facilitates substrate cleavage by the catalytic presenilin subunit in the gamma-secretase complex. One conserved glutamate is especially important, probably because this residue forms an ion pair with the amino terminus of the substrate. This substrate-binding domain is often called the DAP domain (named after DYIGS, the amino acid stretch that modulates amyloid precursor protein (APP) processing, and Peptidase homologous region). The sequence of the substrate N-terminus is apparently not critical for the interaction, but a free amino group is. Thus, nicastrin can be considered a kind of gatekeeper for the gamma-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site. Dysfunction of gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1).
[20, 3, 1, 10, 13, 4, 12, 8, 19, 7, 2, 15, 11, 6, 18, 17, 9, 5, 14, 16]

References

1.Structural basis of human γ-secretase assembly. Sun L, Zhao L, Yang G, Yan C, Zhou R, Zhou X, Xie T, Zhao Y, Wu S, Li X, Shi Y. Proc Natl Acad Sci U S A 112, 6003-8, (2015). PMID: 25918421

2.Nicastrin is a resident lysosomal membrane protein. Bagshaw RD, Pasternak SH, Mahuran DJ, Callahan JW. Biochem. Biophys. Res. Commun. 300, 615-8, (2003). View articlePMID: 12507492

3.Crystal structure of the γ-secretase component nicastrin. Xie T, Yan C, Zhou R, Zhao Y, Sun L, Yang G, Lu P, Ma D, Shi Y. Proc Natl Acad Sci U S A 111, 13349-54, (2014). PMID: 25197054

4.Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior. Dries DR, Zhu Y, Brooks MM, Forero DA, Adachi M, Cenik B, West JM, Han YH, Yu C, Arbella J, Nordin A, Adolfsson R, Del-Favero J, Lu QR, Callaerts P, Birnbaum SG, Yu G. J Biol Chem 291, 11647-56, (2016). PMID: 27008863

5.Metalloaminopeptidases: common functional themes in disparate structural surroundings. Lowther WT, Matthews BW. Chem. Rev. 102, 4581-608, (2002). View articlePMID: 12475202

6.The Zn-peptidase superfamily: functional convergence after evolutionary divergence. Makarova KS, Grishin NV. J. Mol. Biol. 292, 11-7, (1999). View articlePMID: 10493853

7.Overexpression of nicastrin increases Abeta production. Murphy MP, Das P, Nyborg AC, Rochette MJ, Dodson MW, Loosbrock NM, Souder TM, McLendon C, Merit SL, Piper SC, Jansen KR, Golde TE. FASEB J 17, 1138-40, (2003). PMID: 12692078

8.Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. 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. Nature 407, 48-54, (2000). View articlePMID: 10993067

9.Nicastrin, a key regulator of presenilin function, is expressed constitutively in human neural cell lines. Satoh J, Kuroda Y. Neuropathology 21, 115-22, (2001). PMID: 11396676

10.An atomic structure of human γ-secretase. Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. Nature 525, 212-7, (2015). View articlePMID: 26280335

11.Cellular functions of gamma-secretase-related proteins. Haffner C, Haass C. Neurodegener Dis 3, 284-9, (2006). PMID: 17047369

12.Nicastrin, a presenilin-interacting protein, contains an aminopeptidase/transferrin receptor superfamily domain. Fagan R, Swindells M, Overington J, Weir M. Trends Biochem. Sci. 26, 213-4, (2001). View articlePMID: 11295540

13.Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity. Zhang X, Sullivan E, Scimeca M, Wu X, Li YM, Sisodia SS. J Biol Chem 291, 6748-53, (2016). PMID: 26887941

14.Evolutionary families of metallopeptidases. Rawlings ND, Barrett AJ. Meth. Enzymol. 248, 183-228, (1995). View articlePMID: 7674922

15.gamma-Secretase activity requires the presenilin-dependent trafficking of nicastrin through the Golgi apparatus but not its complex glycosylation. Herreman A, Van Gassen G, Bentahir M, Nyabi O, Craessaerts K, Mueller U, Annaert W, De Strooper B. J. Cell. Sci. 116, 1127-36, (2003). View articlePMID: 12584255

16.MEROPS: the peptidase database. Rawlings ND, Morton FR, Barrett AJ. Nucleic Acids Res. 34, D270-2, (2006). View articlePMID: 16381862

17.Nicastrin binds to membrane-tethered Notch. Chen F, Yu G, Arawaka S, Nishimura M, Kawarai T, Yu H, Tandon A, Supala A, Song YQ, Rogaeva E, Milman P, Sato C, Yu C, Janus C, Lee J, Song L, Zhang L, Fraser PE, St George-Hyslop PH. Nat Cell Biol 3, 751-4, (2001). PMID: 11483961

18.Wild-type and mutated nicastrins do not display aminopeptidase M- and B-like activities. Fergani A, Yu G, St George-Hyslop P, Checler F. Biochem Biophys Res Commun 289, 678-80, (2001). PMID: 11726200

19.Degradation of nicastrin involves both proteasome and lysosome. He G, Qing H, Tong Y, Cai F, Ishiura S, Song W. J Neurochem 101, 982-92, (2007). PMID: 17326768

20.Nicastrin: gatekeeper of the gamma-secretase complex. De Strooper B. Cell 122, 318-20, (2005). PMID: 16096051

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