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J. Biol. Chem., Vol. 280, Issue 27, 25892-25900, July 8, 2005

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Spatial Segregation of -Secretase and Substrates in Distinct Membrane Domains^*

Kulandaivelu S. Vetrivel, Haipeng Cheng, Seong-Hun Kim, Ying Chen, Natalie Y. Barnes, Angèle T. Parent, Sangram S. Sisodia, and Gopal Thinakaran

From the Department of Neurobiology, Pharmacology, and Physiology, the University of Chicago, Chicago, Illinois 60637

-Secretase facilitates the regulated intramembrane proteolysis of select type I membrane proteins that play diverse physiological roles in multiple cell types and tissue. In this study, we used biochemical approaches to examine the distribution of amyloid precursor protein (APP) and several additional -secretase substrates in membrane microdomains. We report that APP C-terminal fragments (CTFs) and -secretase reside in Lubrol WX detergent-insoluble membranes (DIM) of cultured cells and adult mouse brain. APP CTFs that accumulate in cells lacking -secretase activity preferentially associate with DIM. Cholesterol depletion and magnetic immunoisolation studies indicate recruitment of APP CTFs into cholesterol- and sphingolipid-rich lipid rafts, and co-residence of APP CTFs, PS1, and syntaxin 6 in DIM patches derived from the trans-Golgi network. Photoaffinity cross-linking studies provided evidence for the preponderance of active -secretase in lipid rafts of cultured cells and adult brain. Remarkably, unlike the case of APP, CTFs derived from Notch1, Jagged2, deleted in colorectal cancer (DCC), and N-cadherin remain largely detergent-soluble, indicative of their spatial segregation in non-raft domains. In embryonic brain, the majority of PS1 and nicastrin is present in Lubrol WX-soluble membranes, wherein the CTFs derived from APP, Notch1, DCC, and N-cadherin also reside. We suggest that -secretase residence in non-raft membranes facilitates proteolysis of diverse substrates during embryonic development but that the translocation of -secretase to lipid rafts in adults ensures processing of certain substrates, including APP CTFs, while limiting processing of other potential substrates.

Received for publication, April 1, 2005 , and in revised form, May 2, 2005.

^* This work was supported in part by National Institutes of Health Grants AG021495, AG019070 (to G. T.), and AG021494 (to S. S. S.), the Alzheimer's Association (to G. T. and A. T. P.), and the American Health Assistance Foundation (to G. T.). 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.

Recipient of a fellowship from the Alzheimer's Disease Research Fund of Illinois Department of Public Health.

To whom correspondence should be addressed: Dept. of Neurobiology, Pharmacology, and Physiology, the University of Chicago, Knapp R212, 924 E. 57th St., Chicago, IL 60637. Tel.: 773-834-3752; Fax: 773-834-3808; E-mail: gopal{at}uchicago.edu.

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