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Originally published In Press as doi:10.1074/jbc.M409272200 on November 29, 2004

J. Biol. Chem., Vol. 280, Issue 6, 4383-4392, February 11, 2005
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{gamma}-Secretase Exists on the Plasma Membrane as an Intact Complex That Accepts Substrates and Effects Intramembrane Cleavage*{boxs}

Jay H. Chyung, Daniel M. Raper, and Dennis J. Selkoe{ddagger}

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

Research on Alzheimer's disease led to the identification of a novel proteolytic mechanism in all metazoans, the presenilin/{gamma}-secretase complex. This unique intramembrane-cleaving aspartyl protease is required for the normal processing of Notch, Jagged, {beta}-amyloid precursor protein (APP), E-cadherin, and many other receptor-like proteins. We recently provided indirect evidence of {gamma}-secretase activity at the cell surface in HeLa cells following inhibition of receptor-mediated endocytosis. Here, we directly identify and isolate {gamma}-secretase as an intact complex (Presenilin, Nicastrin, Aph-1, and Pen-2) from the plasma membrane, both in overexpressing cell lines and endogenously. Inhibition of its proteolytic activity allowed cell surface {gamma}-secretase to be captured in association with its plasma membrane-localized APP substrates (C83 and C99). Moreover, non-denaturing isolation of the intact enzyme complex revealed that cell surface {gamma}-secretase can specifically generate amyloid {beta}-protein from an APP substrate and similarly cleave a Notch substrate. These data directly establish the proteolytic function of {gamma}-secretase on the plasma membrane, independent of a hypothesized substrate trafficking role. We conclude that presenilin/{gamma}-secretase exists as a mature complex at the cell surface, where it interacts with and can cleave its substrates, consistent with an essential function in processing many adhesion molecules and receptors required for cell-cell interaction or intercellular signaling.

Received for publication, August 12, 2004 , and in revised form, October 27, 2004.

* This work was supported by a Lefler Pre-doctoral Fellowship (to J. H. C.), a Albert J. Ryan Fellowship (to J. H. C.), and National Institutes of Health Grants AG 06173 and AG15379 (to D. J. S.). 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.

{boxs} The on-line version of this article (available at http://www.jbc.org) contains Figs. S1–S2 and additional text.

{ddagger} To whom correspondence should be addressed: Harvard Institutes of Medicine–730, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-525-5200; Fax: 617-525-5252; E-mail: Dselkoe{at}rics.bwh.harvard.edu.


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