Modulation of ?-secretase activity by multiple enzyme-substrate interactions: implications in pathogenesis of Alzheimer's disease.

ABSTRACT:

Background

We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease ?-secretase, from the initial interaction with its C99 substrate to the final release of toxic A? peptides.

Results

The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest A?42/A?40 ratio is observed in pre-steady-state when A?40 is the dominant product. A?42 is produced after A?40, and therefore A?42 is not a precursor for A?40. The longer more hydrophobic A? products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of ?-secretase with its C99 substrate leads to 30% decrease in A?40 with concomitant increase in the longer A? products and A?42/A?40 ratio. To different degree the same changes in A? products can be observed with two mutations that lead to an early onset of AD, ?E9 and G384A. Four different lines of evidence show that ?-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, Notch?E substrate can activate or inhibit ?-secretase activity on C99 substrate. Multiple C99 molecules bound to ?-secretase can affect processive cleavages of the nascent A? catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded A?-bundles.

Conclusions

Gradual saturation of ?-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of ?-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded A?-bundles generated by ?-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis.

SUBMITTER: Svedruzic ZM 

PROVIDER: S-EPMC3316526 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature