A Rational Design Strategy for the Selective Activity
Enhancement of a Molecular Chaperone toward a Target Substrate
- Publication date
- Publisher
Abstract
Molecular
chaperones facilitate the folding and assembly of proteins and inhibit their aberrant aggregation. They thus offer several opportunities
for biomedical and biotechnological applications, as for example
they can often prevent protein aggregation more effectively than other
therapeutic molecules, including small molecules and antibodies. Here
we present a method of designing molecular chaperones with enhanced
activity against specific amyloidogenic substrates while leaving
unaltered their functions toward other substrates. The method consists
of grafting onto a molecular
chaperone a peptide designed to bind specifically an epitope in
the target substrate. We illustrate this strategy by describing Hsp70
variants with increased affinities for α-synuclein and Aβ42
but otherwise unaltered affinities for other substrates. These designed
variants inhibit protein aggregation and disaggregate preformed fibrils
significantly more effectively than wild-type Hsp70 indicating that the strategy presented here provides a possible
route for tailoring rationally molecular chaperones for specific purposes