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

Bolduc, David M., Montagna, Daniel R., Gu, Yongli, Selkoe, Dennis J., Wolfe, Michael S.·2016·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1512952113
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Abstract

Significance: γ-Secretase is a conserved and ubiquitous intramembrane-cleaving protease (I-CLiP). Its normal function is required for proper notch signaling, and its processing of amyloid precursor protein is implicated in Alzheimer’s disease. Although γ-secretase has over 90 reported substrates, little is known about the mechanism by which γ-secretase recruits its substrates while at the same time distinguishing substrate from nonsubstrate within the protein-crowded environment of cellular membranes. In contrast to previous studies, our data demonstrate that substrate transmembrane domain drives its interaction with γ-secretase. We find that the γ-secretase component nicastrin acts to sterically block substrates with large ectodomains from interacting with γ-secretase, providing the mechanism by which γ-secretase selectively recruits ectodomain-shed substrates while also preventing cleavage of nonsubstrates.

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  • Normally, the γ-secretase enzyme complex is autoinhibited, and this autoinhibition is removed when substrates are cleaved extracellularly, exposing the transmembrane domain for cleavage by γ-secretase.

    “Normally, the γ-secretase enzyme complex is autoinhibited, and this autoinhibition is removed when substrates are cleaved extracellularly, exposing the transmembrane domain for cleavage by γ-secretase103.”

    From Pathways and Molecular Mechanisms Governing LDL Receptor Regulation (2025) · cites this paper as [103]

    The Discussion (page unavailable) says nicastrin sterically blocks substrates with large ectodomains from entering the γ-secretase active site, explaining why ectodomain shedding is needed before cleavage. The paper supports the substrate-access mechanism, but does not say that shedding removes autoinhibition of the enzyme complex itself; its nicastrin gate remains in place. (LLM, conf=0.86)

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Metadata

Authors
Bolduc, D. M., Montagna, D. R., Gu, Y., Selkoe, D. J., & Wolfe, M. S.
Affiliations
Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2015-12-22
Volume
113
Issue
5
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.1512952113
Cited by
144
References
1
Language
en
Licence
www.pnas.org/preview_site/misc/userlicense.xhtml (vor, 183 d)
Funders
HHS | NIH | National Institute on Aging (P01 AG15379)

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