Processing amyloid precursor protein at the beta-site requires proper orientation to be accessed by BACE1

The Journal of Biological Chemistry
Isam QahwashRiqiang Yan

Abstract

Membrane-bound BACE1 naturally cleaves its transmembrane substrate amyloid precursor protein (APP) at the two adjacent beta- and beta'-sites. Cleavage at these two sites generates the heterogeneous N-terminal end of APP C-terminal fragments that are further processed by gamma-secretase to release Abeta-(1-40/42) or Abeta-(11-40/42). The significance underlying Abeta-(11-40/42) in Alzheimer's disease pathogenesis has remained to be experimentally elucidated, but increased production of Abeta-(1-40/42) has been broadly demonstrated to contribute to amyloid depositions in senile plaques. In this study, we show that the cleavage of APP at the beta-site by BACE1 is readily disrupted through limited structural twists, whereas the beta'-site is relatively better positioned to gain access to the BACE1 catalytic cavity. Radical insertion or deletion of residues between beta- and beta'-site also favors cleavage of APP at the beta'-site. On the other hand, either lengthening or shortening the loop region of BACE1 has a minor impact on the selective cleavage of APP at these two adjacent sites, but significantly shortening the loop region impairs the ability of BACE1 to process APP at both sites. Thus, processing of APP by BACE1 is clearly ...Continue Reading

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Citations

Nov 10, 2009·Cellular and Molecular Life Sciences : CMLS·A RostagnoJorge Ghiso
Jul 12, 2013·Drugs & Aging·Genevieve Evin, Christopher Hince
Jun 15, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Xiangdong ZhouRiqiang Yan
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Jul 9, 2008·Annals of Medicine·Nathalie BrouwersChristine Van Broeckhoven
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Apr 13, 2007·Progress in Neurobiology·Matthias Gralle, Sérgio T Ferreira
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