Journal
STRUCTURE
Volume 22, Issue 7, Pages 996-1007Publisher
CELL PRESS
DOI: 10.1016/j.str.2014.05.003
Keywords
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Funding
- U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH1135]
- NIH [R01 GM81539, P41 GM103622]
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Human presequence protease (hPreP) is an M16 metalloprotease localized in mitochondria. There, hPreP facilitates proteostasis by utilizing an similar to 13,300-angstrom(3) catalytic chamber to degrade a diverse array of potentially toxic peptides, including mitochondrial presequences and beta-amyloid (A beta), the latter of which contributes to Alzheimer disease pathogenesis. Here, we report crystal structures for hPreP alone and in complex with A beta, which show that hPreP uses size exclusion and charge complementation for substrate recognition. These structures also reveal hPreP-specific features that permit a diverse array of peptides, with distinct distributions of charged and hydrophobic residues, to be specifically captured, cleaved, and have their amyloidogenic features destroyed. SAXS analysis demonstrates that hPreP in solution exists in dynamic equilibrium between closed and open states, with the former being preferred. Furthermore, A beta binding induces the closed state and hPreP dimerization. Together, these data reveal the molecular basis for flexible yet specific substrate recognition and degradation by hPreP.
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