HSP70 recognition of exposed β-sheet segments triggers CHIP-mediated selective…

The cellular clearance of amyloidogenic oligomers operates through a two-stage molecular recognition system where exposed β-sheet propensity sequences serve as both HSP70 binding codes and conformational switches for CHIP-mediated degradation. When amyloidogenic proteins misfold into oligomeric intermediates, cryptic hydrophobic stretches (5-15 residues) with high β-sheet forming propensity become solvent-accessible and are recognized by the substrate-binding domain of HSPA8. This initial recognition event induces a distinct conformational change in HSP70 that stabilizes its interaction with CHIP (STUB1) through enhanced TPR-EEVD domain binding. The oligomeric state of the substrate is critical - while monomeric misfolded species may undergo HSP70-mediated refolding, oligomeric conformers present multiple exposed amyloidogenic segments that create a high-avidity binding platform, promoting prolonged CHIP engagement and subsequent polyubiquitination. VCP then extracts these polyubiquitinated oligomers from the HSP70-CHIP complex and delivers them to the 26S proteasome via PSMD4-mediated recognition. This mechanism explains the selective degradation of toxic oligomeric intermediates while preserving refolding capacity for recoverable misfolded monomers. The system’s specificity arises from the conformational switch in HSP70 that occurs only when bound to oligomeric species displaying multiple amyloidogenic recognition sites, thereby functioning as a molecular timer that distinguishes between transiently misfolded proteins requiring refolding assistance versus irreversibly aggregated species requiring elimination.