Influence of Presenilin H1-H2 Linker Mutations on the APP Processing by Gamma-Secretase

Abstract

Gamma-secretase is an aspartyl protease located in membrane bilayer which is composed of four protein units: presenilin, nicastrin, APH-1 and PEN-2. The key groups that are responsible for processing the substrates, aspartic acids 257 and 385, are located in the presenilin unit. Despite the extensive research, the mechanism by which gamma-secretase recognizes and cuts other proteins is still unclear. A detailed insight into this process is on the high importance since aberrant processing of one of the gamma-secretase's substrates- APP- leads to Alzheimer's disease. This abnormal activity results in releasing 42 amino acids long product (Ab-42), which is more prone to aggregate, therefore imparing synaptic activity faster (in contrast of less amyloidogenic, 40 amino acids product). In the identified complex of bCTF APP with gamma-secretase, the substrate is in contact with highly dynamic linker- part of the protein on which there are plenty of mutations that give rise to Ab-42 production. This work focuses on investigating the behaviour of the linker part of presenilin by means of Molecular Dynamics. We examine impact of four different mutations on linker (Y115C, P117A, P117R and E120K), which are known for promoting of Ab-42 releasing. We characterize conformational changes of linker in absence and presence of substrate and show that pre-mentioned mutations cause different arrangement of helices that may alter the binding mode of substrates.