HSP90-CDC37 complex recognizes exposed hydrophobic clusters as amyloidogenic danger signals

The HSP90-CDC37 chaperone complex functions as a specialized surveillance system that recognizes amyloidogenic protein species through detection of exposed hydrophobic clusters rather than individual β-sheet propensity sequences. This mechanism involves HSP90α and HSP90β isoforms operating in conjunction with the co-chaperone CDC37 to identify pathological conformers based on the spatial organization of multiple hydrophobic residues that become simultaneously exposed during misfolding events. Unlike sequential recognition of linear segments, this system detects three-dimensional hydrophobic patches consisting of 8-12 non-contiguous residues that cluster together on the protein surface during aggregation-prone conformational states. The HSP90 N-terminal ATP-binding domain undergoes nucleotide-dependent conformational cycling that modulates the middle domain's ability to recognize these hydrophobic clusters, while CDC37 acts as an adaptor protein that enhances selectivity for aggregation-prone substrates by stabilizing the ATP-bound state of HSP90.

The HSP90-CDC37 chaperone complex functions as a specialized surveillance system that recognizes amyloidogenic protein species through detection of exposed hydrophobic clusters rather than individual β-sheet propensity sequences. This mechanism involves HSP90α and HSP90β isoforms operating in conjunction with the co-chaperone CDC37 to identify pathological conformers based on the spatial organization of multiple hydrophobic residues that become simultaneously exposed during misfolding events. Unlike sequential recognition of linear segments, this system detects three-dimensional hydrophobic patches consisting of 8-12 non-contiguous residues that cluster together on the protein surface during aggregation-prone conformational states. The HSP90 N-terminal ATP-binding domain undergoes nucleotide-dependent conformational cycling that modulates the middle domain's ability to recognize these hydrophobic clusters, while CDC37 acts as an adaptor protein that enhances selectivity for aggregation-prone substrates by stabilizing the ATP-bound state of HSP90. The recognition mechanism is driven by the thermodynamic favorability of burying large hydrophobic surface areas, creating a cooperative binding mode where multiple weak interactions combine to generate high-specificity recognition of amyloidogenic conformers. CDC37's kinase-like domain contributes to substrate discrimination by forming additional contacts with exposed aromatic residues that are characteristic of amyloidogenic regions. This cluster-based recognition system explains the chaperone network's ability to distinguish between normal folding intermediates, which typically expose smaller, more transient hydrophobic patches, and pathological conformers that display larger, more persistent hydrophobic clusters due to their kinetic trapping in aggregation-competent states. The mechanism provides enhanced sensitivity for detecting early-stage oligomeric species that precede fibril formation.