Amyloidogenic segments undergo conformational templating by HSP90-HSP70 heteroc…

The recognition and remodeling of amyloidogenic protein species involves a sequential conformational templating mechanism mediated by HSP90-HSP70 heterocomplexes, where HSP90 serves as the primary conformational sensor while HSP70 provides the refolding machinery. This mechanism centers on HSP90’s unique ability to bind partially folded client proteins through its middle domain, which recognizes the altered global fold topology that occurs when amyloidogenic segments become exposed. Upon HSP90 binding, the chaperone induces a conformational change that further exposes the cryptic β-sheet propensity regions, creating high-affinity binding sites for HSP70 recruitment through the co-chaperone HOP (HSP70-HSP90 organizing protein). The HSP90-HSP70 heterocomplex then orchestrates a coordinated ATP-dependent cycle where HSP90’s conformational constraint maintains the substrate in a refolding-competent state while HSP70 directly engages the exposed amyloidogenic segments. This templating mechanism explains the enhanced specificity for pathological conformers, as HSP90’s client selectivity is determined by global structural perturbations that accompany amyloidogenic segment exposure, while normal folding intermediates lack the sustained conformational alterations required for stable HSP90 engagement. The co-chaperones DNAJB6 and DNAJB2 facilitate this process by stabilizing the heterocomplex and enhancing the cooperative binding to amyloidogenic sequences. This model predicts that HSP90 inhibition would impair the recognition of amyloidogenic species by disrupting the initial conformational sensing step, leading to reduced HSP70 recruitment and compromised quality control of aggregation-prone proteins.