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Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides
dc.contributor.author | Liu, Lei | |
dc.contributor.author | Lauro, Bianca M. | |
dc.contributor.author | Wolfe, Michael S. | |
dc.contributor.author | Selkoe, Dennis J. | |
dc.date.accessioned | 2022-01-06T19:34:57Z | |
dc.date.available | 2022-01-06T19:34:57Z | |
dc.date.issued | 2021-02-08 | |
dc.identifier.citation | Liu, L., Lauro, B. M., Wolfe, M. S., & Selkoe, D. J. (2021). Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides. The Journal of biological chemistry, 296, 100393. https://doi.org/10.1016/j.jbc.2021.100393 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/32356 | |
dc.description.abstract | γ-Secretase is responsible for the proteolysis of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). The biochemical mechanism of how processing by γ-secretase is regulated, especially as regards the interaction between enzyme and substrate, remains largely unknown. Here, mutagenesis reveals that the hydrophilic loop-1 (HL-1) of presenilin-1 (PS1) is critical for both γ-secretase step-wise cleavages (processivity) and its allosteric modulation by heterocyclic γ-modulatory compounds. Systematic mutagenesis of HL-1, including all of its familial AD mutations and additional engineered variants, and quantification of the resultant Aβ products show that HL-1 is necessary for proper sequential γ-secretase processivity. We identify Y106, L113, and Y115 in HL-1 as key targets for heterocyclic γ-secretase modulators (GSMs) to stimulate processing of pathogenic Aβ peptides. Further, we confirm that the GxxxG domain in the APP transmembrane region functions as a critical substrate motif for γ-secretase processivity: a G29A substitution in APP-C99 mimics the beneficial effects of GSMs. Together, these findings provide a molecular basis for the structural regulation of γ-processivity by enzyme and substrate, facilitating the rational design of new GSMs that lower AD-initiating amyloidogenic Aβ peptides. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | en_US |
dc.subject | γ-secretase | en_US |
dc.subject | Aβ | en_US |
dc.subject | Presenilin-1 | en_US |
dc.subject | γ-secretase modulator | en_US |
dc.subject | Alzheimer’s disease | en_US |
dc.title | Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Wolfe, Michael S. | |
kusw.kudepartment | Medical Chemistry | en_US |
dc.identifier.doi | 10.1016/j.jbc.2021.100393 | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0002-4604-4629 | en_US |
dc.identifier.orcid | https://orcid.org/ 0000-0002-5721-9092 | en_US |
kusw.oaversion | Scholarly/refereed, publisher version | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7961089 | en_US |
dc.rights.accessrights | openAccess | en_US |