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000258782 1001_ $$00009-0009-1762-0269$$aChen, Shu-Yu$$b0
000258782 245__ $$aEnzyme-substrate hybrid β-sheet controls geometry and water access to the γ-secretase active site.
000258782 260__ $$aLondon$$bSpringer Nature$$c2023
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000258782 520__ $$aγ-Secretase is an aspartyl intramembrane protease that cleaves the amyloid precursor protein (APP) involved in Alzheimer's disease pathology and other transmembrane proteins. Substrate-bound structures reveal a stable hybrid β-sheet immediately following the substrate scissile bond consisting of β1 and β2 from the enzyme and β3 from the substrate. Molecular dynamics simulations and enhanced sampling simulations demonstrate that the hybrid β-sheet stability is strongly correlated with the formation of a stable cleavage-compatible active geometry and it also controls water access to the active site. The hybrid β-sheet is only stable for substrates with 3 or more C-terminal residues beyond the scissile bond. The simulation model allowed us to predict the effect of Pro and Phe mutations that weaken the formation of the hybrid β-sheet which were confirmed by experimental testing. Our study provides a direct explanation why γ-secretase preferentially cleaves APP in steps of 3 residues and how the hybrid β-sheet facilitates γ-secretase proteolysis.
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000258782 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics
000258782 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism
000258782 650_2 $$2MeSH$$aCatalytic Domain
000258782 650_2 $$2MeSH$$aProtein Conformation, beta-Strand
000258782 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: genetics
000258782 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000258782 650_2 $$2MeSH$$aWater Supply
000258782 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases
000258782 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000258782 7001_ $$0P:(DE-2719)2811962$$aFeilen, Lukas Peter$$b1$$udzne
000258782 7001_ $$00000-0002-8239-559X$$aChávez-Gutiérrez, Lucía$$b2
000258782 7001_ $$0P:(DE-2719)2000023$$aSteiner, Harald$$b3
000258782 7001_ $$00000-0001-5163-2663$$aZacharias, Martin$$b4
000258782 773__ $$0PERI:(DE-600)2919698-X$$a10.1038/s42003-023-05039-y$$gVol. 6, no. 1, p. 670$$n1$$p670$$tCommunications biology$$v6$$x2399-3642$$y2023
000258782 8564_ $$uhttps://www.nature.com/articles/s42003-023-05039-y
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