Distinct J-protein architectures decode exposed β-sheet recognition codes to enable selective pathogenic aggregate targeting

The cellular quality control system operates through a sophisticated molecular recognition mechanism where distinct J-protein co-chaperone architectures serve as specialized decoders for exposed amyloidogenic segments that function as HSP70 recognition codes. When pathological misfolding occurs, cryptic hydrophobic stretches (5-15 residues) with high β-sheet propensity become solvent-accessible and serve as molecular barcodes distinguishing pathogenic conformers from native proteins. DNAJB6's unique structural architecture, featuring serine/threonine-rich domains and glycine/phenylalanine repeats, creates a binding interface specifically optimized for recognizing the regular β-strand spacing (4.8 Å) and cross-β structures characteristic of amyloid aggregates. This architectural specificity enables DNAJB6 to selectively bind exposed amyloidogenic recognition codes while ignoring transiently exposed hydrophobic patches during normal folding. Upon recognition, DNAJB6 recruits HSPA8 or HSPA1A through allosteric ATPase activation, forming a stable disaggregation complex that targets the pathogenic aggregate for dissolution.

The cellular quality control system operates through a sophisticated molecular recognition mechanism where distinct J-protein co-chaperone architectures serve as specialized decoders for exposed amyloidogenic segments that function as HSP70 recognition codes. When pathological misfolding occurs, cryptic hydrophobic stretches (5-15 residues) with high β-sheet propensity become solvent-accessible and serve as molecular barcodes distinguishing pathogenic conformers from native proteins. DNAJB6's unique structural architecture, featuring serine/threonine-rich domains and glycine/phenylalanine repeats, creates a binding interface specifically optimized for recognizing the regular β-strand spacing (4.8 Å) and cross-β structures characteristic of amyloid aggregates. This architectural specificity enables DNAJB6 to selectively bind exposed amyloidogenic recognition codes while ignoring transiently exposed hydrophobic patches during normal folding. Upon recognition, DNAJB6 recruits HSPA8 or HSPA1A through allosteric ATPase activation, forming a stable disaggregation complex that targets the pathogenic aggregate for dissolution. In contrast, DNAJB2's distinct architecture preferentially recognizes different molecular signatures - exposed α-helical intermediates and disordered regions - enabling it to target stress granule components and refolding intermediates through rapid HSP70 cycling. This dual-decoder system creates a sophisticated cellular triage mechanism where the specific J-protein architecture determines substrate fate: DNAJB6-HSP70 complexes target irreversibly misfolded amyloidogenic aggregates for dissolution, while DNAJB2-HSP70 complexes facilitate refolding of transiently misfolded but salvageable proteins. The selectivity emerges from the architectural match between J-protein binding interfaces and the specific geometric and physicochemical signatures of different pathological conformers.