Quantifying correlations between mutational sites in the catalytic subunit of γ-secretase

Abstract

Presenilin 1 (PS1) is the catalytic subunit of the γ-secretase complex which is involved in the generation of amyloid-β peptides (Aβ). Single point mutations in PS1 alter the cleavage pattern of the amyloid precursor protein (APP) and lead to the formation of aberrant Aβ peptides. To date, more than two hundred mutations distributed among almost a third of PS1's amino acids have been associated to the development of Alzheimer's disease (AD). Nevertheless, the mechanism by which mutations far from the catalytic site alter the γ-secretase's cleavage pattern remains unclear. In this work we analyzed correlated motions between amino acids in the wild type (WT) enzyme and 13 γ-secretase mutant models employing a multi-scale molecular dynamics approach. The effect of the protonation state of key catalytic residue Asp385 on the correlation networks was also evaluated. We observed that the strength and number of correlations is highly influenced in all mutant models in both protonation state models. The biggest changes were observed in mutants I83T, W165G, H214Y and L435F; the latest has been proved to drastically reduce γ-secretase activity. Finally, we made a classification of the studied mutations according to their correlation networks with amino acids at: (1) the interfaces with the other γ-secretase components, (2) the catalytic site, (3) the substrate entry site and (4) the substrate recognition site. Overall, this work provides insight into the allosteric communication networks of PS1.

Keywords: Correlation analysis; FAD mutations; Presenilin; γ-Secretase.