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Papers In Press, published online ahead of print March 29, 2004
Dept Cell and Molecular Biology, Karolinska Institutet, Stockholm, S SE-171 77
Corresponding Author: Urban.Lendahl{at}cmb.ki.se
Processing of the Alzheimer amyloid precursor protein (APP) into the amyloid
J. Biol. Chem, 10.1074/jbc.M401277200
Submitted on February 5, 2004
Revised on March 23, 2004
Accepted on March 29, 2004
Functional domains in presenilin 1: the Tyr-288 residue controls
-secretase activity and endoproteolysis
-protein and the APP intracellular domain (AICD) 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 (NTF) and a C-terminal fragment (CTF). Here we aimed at further understanding the role of PS in endoproteolysis, 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 NTF as critical for PS-dependent intramembrane proteolysis. Further mutagenesis of the 288 site identified mutants diff erentially affecting endoproteolysis and -secretase activity. The Y288F mutant was endoproteolyzed to the same extent as wild type PS but increased the Ab42/40 ratio by approximately 75%. In contrast, the Y288N mutant was also endoproteolytically p rocessed 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.
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