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J. Biol. Chem., Vol. 280, Issue 51, 41987-41996, December 23, 2005

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-Secretase Substrate Selectivity Can Be Modulated Directly via Interaction with a Nucleotide-binding Site^*

From the Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

-Secretase is an unusual protease with an intramembrane catalytic site that cleaves many type I membrane proteins, including the amyloid -protein (A) precursor (APP) and the Notch receptor. Genetic and biochemical studies have identified four membrane proteins as components of -secretase: heterodimeric presenilin composed of its N- and C-terminal fragments, nicastrin, Aph-1, and Pen-2. Here we demonstrated that certain compounds, including protein kinase inhibitors and their derivatives, act directly on purified -secretase to selectively block cleavage of APP- but not Notch-based substrates. Moreover, ATP activated the generation of the APP intracellular domain and A, but not the generation of the Notch intracellular domain by the purified protease complex, and was a direct competitor of the APP-selective inhibitors, as were other nucleotides. In accord, purified -secretase bound specifically to an ATP-linked resin. Finally, a photoactivable ATP analog specifically labeled presenilin 1-C-terminal fragments in purified -secretase preparations; the labeling was blocked by ATP itself and APP-selective -secretase inhibitors. We concluded that a nucleotide-binding site exists within -secretase, and certain compounds that bind to this site can specifically modulate the generation of A while sparing Notch. Drugs targeting the -secretase nucleotide-binding site represent an attractive strategy for safely treating Alzheimer disease.

Received for publication, February 4, 2005 , and in revised form, October 16, 2005.

^* This work was supported by Swiss National Science Foundation Grant 81FR-68842 (to P. C. F.), NIA Grant AG15379 from the National Institutes of Health, a Pioneer award from the Alzheimer Association (to D. J. S.), and by National Institutes of Health Grants AG17574, AG15379, and NS41355 (to M. S. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Table S1.

¹ To whom correspondence may be addressed: Center for Neurologic Diseases, Harvard Institute of Medicine, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5200; Fax: 617-525-5252; E-mail: dselkoe{at}rics.bwh.harvard.edu. ² To whom correspondence may be addressed. E-mail: mwolfe{at}rics.bwh.harvard.edu.

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