Through a nice piece of protein chemistry work, Yu and colleagues from Peter St. George Hyslop’s laboratory have shown that a novel protein, named nicastrin, associates with preseniln 1 and presenilin 2 (Yu et al., 2000). Surprisingly, this association of nicastrin and presenilins affects APP processing and Aβ generation. That other molecules may be associated with the presenilins has been suspected for some time since the PS complex has been estimated to be from 250,000-over one million kDa.
Nicastrin is a 75 kDa protein that was isolated at stoichiometric levels to PS1. Engineered amino acid substitutions of nicastrin at the DYIGS motif that is conserved between the nicastrin homologs, enhanced release of both Aβ40 and Aβ42. Deletion mutants of DYIGS paradoxically reduced Aβ production, a situation that has been described at certain positions in PS1. In C. elegans, reduced activity of the nicastrin homolog produced notch/glp-1 phenotypes, consistent with the concept that nicastin may facilitate Notch and APP proteolysis. From these intriguing first set of results, much work needs to be done.
Nevertheless, it certainly indicates that a functional complex consisting of presenilins and nicastrin work in coordination to facilitate Notch and APP signaling. It also indicates that simple reconstitution of presenilins and APP (or notch) is unlikely to demonstrate biological activity. For those who believe that presenilins are γ-secretases, this report is not against that notion. For those who feel that presenilins are not the actual γ-secretases, this report suggests that there is much more behind how presenilins work. Indeed, the full complex has yet to be fully eludicated and the actual protease activity remains to be discovered.—Eddie Koo
- 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. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing. Nature. 2000 Sep 7;407(6800):48-54. PubMed.