Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides
| العنوان: | Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides |
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| المؤلفون: | Dennis J. Selkoe, Lei Liu, Michael S. Wolfe, Bianca M. Lauro |
| المصدر: | The Journal of Biological Chemistry |
| بيانات النشر: | American Society for Biochemistry and Molecular Biology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, FAD, familial Alzheimer’s disease, HL-1, hydrophilic loop-1, Amyloid beta, Allosteric regulation, TMD, transmembrane domain, γ-secretase, AD, Alzheimer’s disease, Biochemistry, Presenilin, DMEM, Dulbecco’s modified Eagle’s medium, Substrate Specificity, 03 medical and health sciences, Amyloid beta-Protein Precursor, FBS, fetal bovine serum, Protein Domains, APP, amyloid precursor protein, Alzheimer Disease, Amyloid precursor protein, Presenilin-1, Humans, Genetic Predisposition to Disease, Molecular Biology, γ-secretase modulator, Cells, Cultured, Aβ, GSM, γ-secretase modulator, CM, conditioned media, Amyloid beta-Peptides, 030102 biochemistry & molecular biology, biology, Chemistry, Rational design, Cell Biology, Processivity, Transmembrane protein, Cell biology, Aβ, amyloid-beta, Transmembrane domain, 030104 developmental biology, PS1, presenilin-1, Mutation, Proteolysis, biology.protein, HMW, high-molecular-weight, Amyloid Precursor Protein Secretases, Alzheimer’s disease, Research Article |
| الوصف: | 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. |
| اللغة: | English |
| تدمد: | 1083-351X 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::534c8ae904c2652969945c575f9df201Test http://europepmc.org/articles/PMC7961089Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....534c8ae904c2652969945c575f9df201 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1083351X 00219258 |
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