Chaperonopathies as Disorders of Disorder: The Role of Intrinsically Disordered Regions in Proteostasis Dysfunction.

Molecular chaperones are central regulators of the proteostasis network, ensuring proteome integrity through protein folding, the prevention of aggregation, and targeted degradation. These mechanisms are essential for limiting proteotoxic stress and preventing the accumulation of pathogenic proteins. Consequently, chaperone dysfunction is linked to various diseases including genetic chaperonopathies caused by pathogenic mutations. The most commonly affected chaperones include small heat shock proteins (sHSPs; HSPB1, HSPB3, HSPB5, HSPB8), Hsp60 (HSPD1), Hsp70 (HSPA9/mortalin), and the CCT/TRiC complex. sHSPs are ATP-independent chaperones critical under stress conditions and are characterized by intrinsically disordered regions (IDRs), particularly in flexible terminal regions. Although structurally important, IDRs are frequently targets of disease-associated mutations. In this study, intrinsic disorder in chaperones linked to genetic chaperonopathies was analyzed using bioinformatics tools, followed by a focused evaluation of highly disordered proteins and their disease associations. The results highlight intrinsic disorder as a conserved and functionally essential feature. HSPB1 and HSPB8 show high disorder levels, consistent with roles in neural proteostasis and neuropathies. HSPB3 and HSPB5 exhibit moderate disorder but harbor mutations linked to muscle and cardiac diseases. In contrast, HSPB6 dysfunction is mainly driven by post-translational modifications, rather than mutations. Overall, genetic chaperonopathies can be viewed as intrinsic-disorder-related diseases.