Aggregation-prone sequences trigger HSP90-dependent conformational triage throu…

The cellular response to amyloidogenic protein species involves a sophisticated HSP90-dependent conformational triage system that modulates key signaling kinases through CDC37-mediated substrate selection, fundamentally altering the protein quality control landscape. This mechanism centers on HSP90’s unique ability to recognize aggregation-prone sequences through its middle domain, which contains a cryptic binding site that becomes accessible upon interaction with misfolded clients bearing exposed β-sheet propensity regions. Unlike the direct chaperoning approach of HSP70, HSP90 functions as a conformational sensor that redistributes cellular proteostasis resources by selectively stabilizing or destabilizing key kinase clients involved in stress response pathways. The co-chaperone CDC37 plays a pivotal role by competing with amyloidogenic substrates for HSP90 binding, creating a molecular switch where increasing levels of misfolded proteins progressively sequester HSP90 away from essential kinase maturation processes. This sequestration triggers a cascade of kinase inactivation, particularly affecting clients like AKT1, CDK4, and EGFR, which normally require HSP90-CDC37 complexes for proper folding and stability. The resulting kinase network perturbation serves as an early warning system that precedes visible protein aggregation, enabling cells to initiate protective responses including autophagy upregulation, translational shutdown, and apoptotic priming. This triage mechanism explains why amyloidogenic diseases often exhibit complex signaling defects that precede overt protein deposition, as the cellular kinome becomes progressively dysregulated through competitive sequestration of the HSP90 machinery by accumulating misfolded species.