Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song Y Q, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang D S, Holmes E, Milman P, Liang Y, Zhang D M, Xu D H, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer L S, Sorbi S, Bruni A, Fraser P, St George-Hyslop P
Centre for Research in Neurodegenerative Diseases, Toronto Western Hospital, and Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
Nature. 2000 Sep 7;407(6800):48-54. doi: 10.1038/35024009.
Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP.
尼卡斯特林是一种跨膜糖蛋白，与早老素1和早老素2形成高分子量复合物。在秀丽隐杆线虫胚胎中抑制尼卡斯特林的表达会诱导出一部分Notch/glp-1表型，类似于秀丽隐杆线虫两种早老素同源物（sel-12和hop-1）同时发生无效突变所诱导的表型。尼卡斯特林还能结合β-淀粉样前体蛋白（βAPP）的羧基末端衍生物，并调节这些衍生物产生淀粉样β肽（Aβ）。尼卡斯特林保守亲水区的错义突变会增加Aβ42和Aβ40肽的分泌。该区域的缺失会抑制Aβ的产生。因此，尼卡斯特林和早老素可能是多聚体复合物的功能成分，该复合物对于Notch/GLP-1和βAPP等蛋白质的膜内蛋白水解是必需的。
