Membrane enzyme cuts a fine figure

Abstract

Malfunction of presenilin enzymes, which cleave proteins in cell membranes, can lead to Alzheimer's disease. A crystal structure of a microbial presenilin provides insights into the workings of this enzyme family. See Article p.56 Presenilin — the catalytic component of γ-secretase — and signal peptide peptidase are intramembrane aspartyl proteases that regulate important biological functions in eukaryotes. The most well-known substrate of γ-secretase is amyloid precursor protein which, when cleaved by γ- and β-secretase, produces the short peptide that can form the amyloid plaques in the brains of Alzheimer's disease patients. In this manuscript, the authors report the X-ray crystal structure of a presenilin/signal peptide peptidase homologue, which reveals that the two catalytic aspartate residues are located approximately 8 Å into the lipid membrane surface. This structure will serve as a framework for understanding the mechanisms of action of presenilin, γ-secretase and signal peptide peptidase