Isoform-selective Genetic Inhibition of Constitutive Cytosolic XXXX Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement.

@entity1 @entity4041 @entity5085 @entity2285 @entity857 @entity1457 @entity2036 @entity13859 @entity9487 @entity4334
The constitutively expressed @entity1457 protein 70 kDa ( @entity9487 ) is a major chaperone protein responsible for maintaining @entity5085 , yet how its structure translates into functional decisions regarding client fate is still unclear. We previously showed that @entity9487 preserved aberrant Tau, but it remained unknown if selective inhibition of the activity of this @entity2285 isoform could facilitate Tau clearance. Using single point mutations in the @entity4334 binding domain, we assessed the effect of several mutations on the functions of @entity1 @entity9487 . Biochemical characterization revealed that one mutation abolished both @entity9487 ATPase and refolding activities. This variant resembled the @entity857 -bound conformer at all times yet remained able to interact with cofactors, @entity2036 , and substrates appropriately, resembling a dominant negative @entity9487 (DN- @entity9487 ). We then assessed the effects of this DN- @entity9487 on its client Tau. DN- @entity9487 potently facilitated Tau clearance via the proteasome in cells and brain tissue, in contrast to wild type @entity9487 that stabilized Tau. Thus, DN- @entity9487 mimics the action of small molecule pan @entity2285 inhibitors with regard to Tau metabolism. This shift in @entity9487 function by a single point mutation was the result of a change in the chaperome associated with @entity9487 such that DN- @entity9487 associated more with @entity4041 and DnaJ proteins, whereas wild type @entity9487 was more associated with other @entity2285 isoforms. Thus, isoform-selective targeting of @entity9487 could be a viable therapeutic strategy for @entity13859 and possibly lead to new insights in chaperone complex biology.
