PerspectiveStructural Biology

Pathology-linked protease caught in action

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Science  15 Feb 2019:
Vol. 363, Issue 6428, pp. 690-691
DOI: 10.1126/science.aaw5547

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Summary

The intramembrane protease γ-secretase has fundamental functions in animals, including signal transduction during embryogenesis and tissue homeostasis in adulthood. γ-Secretase cleaves its numerous substrates within their single transmembrane domains (TMDs), largely independently of their amino acid sequence. Abnormal cleavage of the substrates Notch and amyloid precursor protein (APP) is linked to leukemia and Alzheimer's disease (AD), respectively, making γ-secretase an important drug target for both diseases (1). Yet, chronic use of γ-secretase inhibitors (GSIs), such as in patients with AD, led to severe side effects, resulting from cleavage inhibition not only of the disease-relevant substrate APP but likely also of other substrates. Thus, there is a clear need to develop substrate-selective GSIs, but this requires a detailed understanding of how γ-secretase recognizes, binds, and cleaves its substrates. On page 708 of this issue, Zhou et al. (2) and another study by Yang et al. (3) provide a major step in this direction. Zhou et al. reveal the cryo–electron microscopy (cryo-EM) structure of human γ-secretase with its bound substrate, a fragment of APP. Yang et al. report a structure of γ-secretase, but bound with Notch. Together, the two studies demonstrate that binding of different substrates occurs in a similar manner and that both γ-secretase and substrate undergo specific structural rearrangements for substrate positioning in the active site. This has major implications for understanding the mechanism of γ-secretase and its function in signal transduction and AD, and for future development of substrate-specific GSIs with fewer side effects.