ArticleCommunications biology2022
A thermodynamic investigation of amyloid precursor protein processing by human γ-secretase.
Article in Communications biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 17 citations in OpenAlex.
- MSCMF-DTB: a multi-scale cross-modal fusion framework for drug-target binding prediction.Scientific reports · 2026Article
- Synthesis, Antimalarial Activity and Molecular Dynamics Studies of Pipecolisporin: A Novel Cyclic Hexapeptide with Potent Therapeutic Potential.Molecules (Basel, Switzerland) · 2025Article
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Molecular mechanisms of NaBiophysical journal · 2024Article
- Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease.Aging and disease · 2024Review
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
- Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein.Communications biology · 2023Article
- How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2.RSC advances · 2023Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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, the L33-V34 scissile bond is more easily hijacked by D257/D385 than T32-L33, resulting in higher Aβ49 cleavage, while the T32N mutation on the APP TMD decreases the energy barrier of the sliding of the scissile bonds and increases the hydrogen bond occupancy for Aβ48 cleavage. In summary, the thermodynamic analysis elucidates possible mechanisms of APP TMD processing by PS1, which might facilitate rational drug design targeting γ-secretase.
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