This study, co-authored by researchers from Bio2Q, the University of Wroclaw, and Heidelberg University, reveals how human cells assemble powerful protein disaggregation machinery to remove potentially harmful protein aggregates. In human cells, this process relies on Hsp70 chaperones working together with J-domain proteins (JDPs), including the class A protein DNAJA2 and class B protein DNAJB1, which form mixed-class assemblies that enhance protein disaggregation.

Here, the researchers investigated how these assemblies achieve their increased activity and found that both JDP partners must actively recruit Hsp70 for efficient disaggregation. Using biochemical assays with mutant JDPs, they showed that formation of the mixed-class scaffold alone is not sufficient, and that disrupting Hsp70 recruitment by either DNAJA2 or DNAJB1 eliminates the synergistic increase in disaggregation. The researchers also found that DNAJA2 and DNAJB1 preferentially process different types of protein aggregates, while their combined assembly expands the range of aggregates that can be effectively handled.

Together, these findings reveal that mixed-class JDP scaffolds enhance protein quality control through two complementary functions, broadening aggregate recognition and enabling multivalent recruitment of Hsp70, and provide new mechanistic insight into how human cells maintain protein homeostasis.