Elucidating the Protonation State of the γ-Secretase Catalytic Dyad

Autor: Dulce C. Guzmán-Ocampo, Rodrigo Aguayo-Ortiz, José-Luis Velasco-Bolom, Pancham Lal Gupta, Adrian E. Roitberg, Laura Dominguez
Rok vydání: 2022
Předmět:
Zdroj: ACS chemical neuroscience.
ISSN: 1948-7193
Popis: γ-Secretase (GS) is an intramembrane aspartyl protease that participates in the sequential cleavage of C99 to generate different isoforms of the amyloid-β (Aβ) peptides that are associated with the development of Alzheimer's disease. Due to its importance in the proteolytic processing of C99 by GS, we performed pH replica exchange molecular dynamics (pH-REMD) simulations of GS in its apo and substrate-bound forms to sample the protonation states of the catalytic dyad. We found that the catalytic dyad is deprotonated at physiological pH in our apo form, but the presence of the substrate at the active site displaces its monoprotonated state toward physiological pH. Our results show that Asp257 acts as the general base and Asp385 as the general acid during the cleavage mechanism. We identified different amino acids such as Lys265, Arg269, and the PAL motif interacting with the catalytic dyad and promoting changes in its acid-base behavior. Finally, we also found a significant pK
Databáze: OpenAIRE