J-protein co-chaperone repertoire drives ATP-independent disaggregation through…

The J-protein co-chaperone system operates through a novel ATP-independent disaggregation mechanism that localizes pathogenic protein recognition to specific membrane compartments. Rather than relying on HSP70 ATPase cycling, DNAJB6 and DNAJB2 form constitutively active membrane-associated complexes at the endoplasmic reticulum and mitochondrial surfaces through direct lipid interactions via their amphipathic helices. DNAJB6’s S/T-rich domain contains cryptic membrane-binding motifs that become exposed upon interaction with β-sheet aggregates, anchoring the chaperone-substrate complex to ER membranes where co-localized proteolytic machinery can access misfolded targets. This spatial sequestration mechanism enables selective aggregate processing without depleting cytosolic chaperone resources. DNAJB2 exhibits preferential association with mitochondrial outer membranes through its unique N-terminal membrane-targeting sequence, where it coordinates with HSPA8 to form disaggregation platforms adjacent to mitochondrial protein import machinery. The membrane-localized J-protein complexes utilize mechanical tension generated by lipid phase transitions and membrane curvature changes to destabilize protein aggregates through conformational strain rather than ATP hydrolysis. This mechanism explains the observed cell-type specificity of aggregate clearance, as different cell types exhibit distinct membrane compositions that modulate J-protein membrane affinity. The hypothesis predicts that membrane cholesterol content and phospholipid composition directly regulate disaggregation efficiency, and that disruption of membrane integrity abolishes selective aggregate recognition while preserving normal protein folding assistance.