A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase.

ABSTRACT: Human γ-secretase cleaves the transmembrane domains (TMDs) of amyloid precursor protein (APP) into pathologically relevant amyloid-β peptides (Aβs). The detailed mechanisms of the unique endoproteolytic cleavage by the presenilin 1 domain (PS1) of γ-secretase are still poorly understood. Herein, we provide thermodynamic insights into how the α-helical APP TMD is processed by γ-secretase and elucidate the specificity of Aβ48/Aβ49 cleavage using unbiased molecular dynamics and bias-exchange metadynamics simulations. The thermodynamic data show that the unwinding of APP TMD is driven by water hydration in the intracellular pocket of PS1, and the scissile bond T32-L33 or L33-V34 of the APP TMD can slide down and up to interact with D257/D385 to achieve endoproteolysis. In the wild-type system,

SUBMITTER: Lu X 

PROVIDER: S-EPMC9388646 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature