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J. Biol. Chem., Vol. 279, Issue 23, 23925-23932, June 4, 2004

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Functional Domains in Presenilin 1

THE TYR-288 RESIDUE CONTROLS -SECRETASE ACTIVITY AND ENDOPROTEOLYSIS^*

Hanna Laudon, Helena Karlström, Paul M. Mathews¶, Mark R. Farmery, Samuel E. Gandy||, Johan Lundkvist, Urban Lendahl, and Jan Näslund**

From the Department of Neurotec, Division of Experimental Geriatrics, Karolinska Institutet, Novum, SE-141 86 Huddinge, Sweden, Department of Cell and Molecular Biology, Karolinska Institutet, The Medical Nobel Institute, SE-171 77 Stockholm, Sweden, ^¶Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York 10962, and ^||Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Processing of the Alzheimer amyloid precursor protein (APP) into the amyloid -protein and the APP intracellular domain is a proteolysis event mediated by the -secretase complex where presenilin (PS) proteins are key constituents. PS is subjected to an endoproteolytic cleavage, generating a stable heterodimer composed of an N-terminal and a C-terminal fragment. Here we aimed at further understanding the role of PS in endoproteolysis, in proteolytic processing of APP and Notch, and in assembly of the -secretase complex. By using a truncation protocol and alanine scanning, we identified Tyr-288 in the PS1 N-terminal fragment as critical for PS-dependent intramembrane proteolysis. Further mutagenesis of the 288 site identified mutants differentially affecting endoproteolysis and -secretase activity. The Y288F mutant was endoproteolyzed to the same extent as wild type PS but increased the amyloid -protein 42/40 ratio by 75%. In contrast, the Y288N mutant was also endoproteolytically processed but was inactive in reconstituting -secretase in PS null cells. The Y288D mutant was deficient in both endoproteolysis and -secretase activity. All three mutant PS1 molecules were incorporated into -secretase complexes and stabilized Pen-2 in PS null cells. Thus, mutations at Tyr-288 do not affect -secretase complex assembly but can differentially control endoproteolysis and -secretase activity.

Received for publication, February 5, 2004 , and in revised form, March 23, 2004.

^* The work was supported in part by grants from Loo och Hans Ostermans Stiftelse, Stiftelsen Gamla Tjänarinnor, Åke Wibergs Stiftelse, Gun och Bertil Stohnes Stiftelse, Stiftelsen Clas Groschinskys Minnesfond, Fonden för Åldersforskning vid Karolinska Institutet, Petrus och Augusta Hedlunds Stiftelse, Alzheimerfonden, Swedish Cancer Society, EU (EuroStemCell), the Swedish Research Council, the Juvenile Diabetes Research Foundation, the Human Frontiers Science Program, and NIA, National Institutes of Health. 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.

^** To whom correspondence should be addressed: Karolinska Institutet, Novum Kaspac pl. 5, SE-141 57 Huddinge, Sweden. Tel.: 46-8-585-835-01; Fax: 46-8-585-836-10; E-mail: jan.naslund{at}neurotec.ki.se.

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