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Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):E509-18. doi: 10.1073/pnas.1512952113. Epub 2015 Dec 22.

Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain.

Author information

1
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
2
Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 mswolfe@partners.org dselkoe@partners.org.

Abstract

γ-Secretase is an intramembrane-cleaving protease that processes many type-I integral membrane proteins within the lipid bilayer, an event preceded by shedding of most of the substrate's ectodomain by α- or β-secretases. The mechanism by which γ-secretase selectively recognizes and recruits ectodomain-shed substrates for catalysis remains unclear. In contrast to previous reports that substrate is actively recruited for catalysis when its remaining short ectodomain interacts with the nicastrin component of γ-secretase, we find that substrate ectodomain is entirely dispensable for cleavage. Instead, γ-secretase-substrate binding is driven by an apparent tight-binding interaction derived from substrate transmembrane domain, a mechanism in stark contrast to rhomboid--another family of intramembrane-cleaving proteases. Disruption of the nicastrin fold allows for more efficient cleavage of substrates retaining longer ectodomains, indicating that nicastrin actively excludes larger substrates through steric hindrance, thus serving as a molecular gatekeeper for substrate binding and catalysis.

KEYWORDS:

Azheimer’s disease; intramembrane-cleaving protease; nicastrin; notch; γ-secretase

Comment in

PMID:
26699478
PMCID:
PMC4747693
DOI:
10.1073/pnas.1512952113
[Indexed for MEDLINE]
Free PMC Article

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