Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.

ABSTRACT: Aberrant cleavage of amyloid precursor protein (APP) by ?-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of ?-secretase), making modulation of ?-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact ?-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to ?-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into A?42, A?40, and A?38. The molar ratio of the cleavage products A?42 over A?40 by PSH is nearly identical to that by ?-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of ?-secretase also modulate PSH similarly in terms of the A?42/A?40 ratio. Structural analysis reveals association of a known ?-secretase inhibitor with PSH between its two catalytic aspartate residues. These findings identify PSH as a surrogate protease for the screening of agents that may regulate the protease activity and the cleavage preference of ?-secretase.

SUBMITTER: Dang S 

PROVIDER: S-EPMC4371958 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature