Structural highlights
FunctionPublication Abstract from PubMedAberrant cleavage of amyloid precursor protein (APP) by gamma-secretase contributes to the development of Alzheimer's disease. More than 200 disease-derived mutations have been identified in presenilin (the catalytic subunit of gamma-secretase), making modulation of gamma-secretase activity a potentially attractive therapeutic opportunity. Unfortunately, the technical challenges in dealing with intact gamma-secretase have hindered discovery of modulators and demand a convenient substitute approach. Here we report that, similar to gamma-secretase, the archaeal presenilin homolog PSH faithfully processes the substrate APP C99 into Abeta42, Abeta40, and Abeta38. The molar ratio of the cleavage products Abeta42 over Abeta40 by PSH is nearly identical to that by gamma-secretase. The proteolytic activity of PSH is specifically suppressed by presenilin-specific inhibitors. Known modulators of gamma-secretase also modulate PSH similarly in terms of the Abeta42/Abeta40 ratio. Structural analysis reveals association of a known gamma-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 gamma-secretase. Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.,Dang S, Wu S, Wang J, Li H, Huang M, He W, Li YM, Wong CC, Shi Y Proc Natl Acad Sci U S A. 2015 Mar 2. pii: 201502150. PMID:25733893[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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