J-protein substrate specificity codes enable HSP70 discrimination of β-sheet ve…

The HSP70 chaperone system achieves selective recognition of pathogenic protein conformers through a sophisticated client code mechanism where J-protein co-chaperones DNAJB6 and DNAJB2 exhibit distinct molecular recognition patterns for different misfolded structures. DNAJB6 contains specialized structural domains—serine/threonine-rich regions and glycine/phenylalanine repeats—that create a binding interface optimized for recognizing exposed β-sheet propensity sequences (5-15 residues) characteristic of amyloidogenic proteins. These cryptic hydrophobic stretches, normally buried in native protein cores, become accessible during pathological misfolding and present the specific 4.8 Å β-strand spacing that DNAJB6’s architecture is evolved to detect. Upon recognition, DNAJB6 recruits HSPA8 or HSPA1A to form stable disaggregation complexes targeting amyloid cores and polyglutamine expansions. In contrast, DNAJB2 operates through fundamentally different binding kinetics, preferentially engaging α-helical intermediates and disordered regions typical of transiently misfolded native proteins. The DNAJB2-HSP70 complex functions via rapid association-dissociation cycles optimized for protein refolding rather than aggregate dissolution. This dual recognition system creates a molecular triage mechanism where the J-protein co-chaperone repertoire serves as the primary determinant of substrate selectivity, enabling HSP70 to distinguish between proteins requiring refolding assistance versus those requiring disaggregation or degradation. The specificity emerges from the differential affinity of J-protein domains for β-sheet versus α-helical structural motifs, providing cells with precise quality control over distinct misfolding pathways.