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Dominant missense mutations in PS1 cause early-onset familial Alzheimer\u2019s disease (FAD); however, the exact pathogenic mechanism remains unknown. Here we combined Gaussian\u00a0accelerated molecular dynamics (GaMD) simulations and biochemical experiments to determine the effects of six representative PS1 FAD mutations (P117L, I143T, L166P, G384A, L435F, and L286V) on the enzyme-substrate interactions between \u03b3-secretase and amyloid precursor protein (APP). Biochemical experiments showed that all six PS1 FAD mutations rendered \u03b3-secretase less active for the endoproteolytic (\u03b5) cleavage of APP. Distinct low-energy conformational states were identified from the free energy profiles of wildtype and PS1 FAD-mutant \u03b3-secretase. The P117L and L286V FAD mutants could still sample the \u201cActive\u201d state for substrate cleavage, but with noticeably reduced conformational space compared with the wildtype. The other mutants hardly visited the \u201cActive\u201d state. The PS1 FAD mutants were found to reduce \u03b3-secretase proteolytic activity by hindering APP residue L49 from proper orientation in the active site and\/or disrupting the distance between the catalytic aspartates. Therefore, our findings provide mechanistic insights into how PS1 FAD mutations affect structural dynamics and enzyme-substrate interactions of \u03b3-secretase and APP.<\/jats:p>","DOI":"10.1038\/s42003-023-04539-1","type":"journal-article","created":{"date-parts":[[2023,2,14]],"date-time":"2023-02-14T08:05:19Z","timestamp":1676361919000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Effects of presenilin-1 familial Alzheimer\u2019s disease mutations on \u03b3-secretase activation for cleavage of amyloid precursor protein"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6497-4096","authenticated-orcid":false,"given":"Hung N.","family":"Do","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujan","family":"Devkota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apurba","family":"Bhattarai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-9092","authenticated-orcid":false,"given":"Michael S.","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3714-1395","authenticated-orcid":false,"given":"Yinglong","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,2,14]]},"reference":[{"key":"4539_CR1","doi-asserted-by":"publisher","first-page":"102373","DOI":"10.1016\/j.sbi.2022.102373","volume":"74","author":"MS Wolfe","year":"2022","unstructured":"Wolfe, M. 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