title: Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain.
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.
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: David M
authors.initials: DM
authors.lastname: Bolduc
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Montagna
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 mswolfe@partners.org dselkoe@partners.org.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Selkoe
authors.affiliation: Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115 mswolfe@partners.org dselkoe@partners.org.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism* / Q000502:physiology; D008051:Lipid Bilayers; D008562:Membrane Glycoproteins / Q000502:physiology*; D013379:Substrate Specificity
chemical_list: D008051:Lipid Bilayers; D008562:Membrane Glycoproteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases
keywords: Azheimer’s disease; intramembrane-cleaving protease; nicastrin; notch; γ-secretase