Structural Biology

Molecular insights into Alzheimer's

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Science  03 Oct 2014:
Vol. 346, Issue 6205, pp. 51
DOI: 10.1126/science.346.6205.51-f
Ribbon diagram of nicastrin. CREDIT: T. XIE ET AL. PNAS 111, 37 (16 SEPTEMBER 2014) © 2014 NATIONAL ACADEMY OF SCIENCES

An intramembrane protein called γ-secretase cleaves amyloid precursor protein (APP) to generate amyloid-β peptides. These peptides clump together to form the plaques found in the brains of people with Alzheimer's disease. Modulating the activity of the γ-secretase might be a useful strategy in treating Alzheimer's disease. Lu et al. recently reported the atomic resolution structure of an intact human γ-secretase complex. Now Xie et al. report an atomic resolution structure of eukaryotic nicastrin, the largest component of γ-secretase. Analysis of the structure suggests a model for how nicastrin recruits APP for cleavage by a second component of the complex. These structures may provide important insights for the design of much needed-new drug candidates.

Nature 512, 166 (2014); Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1414837111 (2014).

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