Nature Cell Biology
2, 428 - 434 (2000)
Published online: 9 June 2000; | doi:10.1038/35017062
Transition-state analogue inhibitors of  -secretase bind directly
to presenilin-1William P. Esler1, W. Taylor Kimberly1, Beth L. Ostaszewski1, Thekla S. Diehl1, Chad L. Moore2, Jui-Yi Tsai1, Talat Rahmati1, Weiming Xia1, Dennis J. Selkoe1
& Michael S. Wolfe1, 21
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital,
77 Avenue Louis Pasteur, Boston, Massachusetts, 02115, USA
2
Department of Pharmaceutical Sciences, University of Tennessee, 847 Monroe Avenue, Memphis, Tennessee, 38163, USA
Correspondence should be addressed to Michael S. Wolfe wolfe@cnd.bwh.harvard.eduThe  -amyloid precursor protein (-APP), which is involved in the
pathogenesis of Alzheimer's disease, and the Notch receptor, which is
responsible for critical signalling events during development, both undergo
unusual proteolysis within their transmembrane domains by unknown  -secretases.
Here we show that an affinity reagent designed to interact with the active
site of -secretase binds directly and specifically to heterodimeric forms
of presenilins, polytopic proteins that are mutated in hereditary Alzheimer's
and are known mediators of -secretase cleavage of both -APP and
Notch. These results provide evidence that heterodimeric presenilins contain
the active site of -secretase, and validate presenilins as principal
targets for the design of drugs to treat and prevent Alzheimer's disease.
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