Exposed amyloidogenic segments trigger CHIP-mediated oligomer-selective ubiquit…

This hypothesis proposes that HSP70’s recognition of exposed β-sheet propensity sequences in amyloidogenic proteins serves as the molecular trigger for CHIP-mediated selective degradation of pathological oligomers. When amyloidogenic segments (typically 5-15 hydrophobic residues with high β-sheet propensity) become exposed during protein misfolding, they are recognized by HSPA8’s substrate-binding domain through their distinct physicochemical properties. This recognition event induces a specific conformational change in HSP70 that acts as a molecular switch, stabilizing the HSP70-CHIP complex through enhanced TPR-EEVD interactions and allosteric modifications of the ATPase domain. The key insight is that oligomeric pathological conformers expose multiple amyloidogenic segments simultaneously, creating a multivalent binding surface that prolongs HSP70-CHIP engagement compared to monomeric species or transient folding intermediates. This sustained complex formation promotes polyubiquitination of lysine residues on the oligomeric substrate through CHIP’s U-box E3 ligase activity. VCP then extracts these polyubiquitinated oligomers from the chaperone complex and delivers them to the 26S proteasome via PSMD4-mediated recognition. The selectivity mechanism operates through a threshold effect: only proteins presenting multiple exposed amyloidogenic sequences (characteristic of pathological oligomers) can maintain sufficient HSP70-CHIP complex stability to trigger degradation, while native proteins or early misfolding intermediates with fewer exposed segments undergo attempted refolding instead.