Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation

An efficient protein disaggregation system uncovered in metazoan cells requires transient interactions between J-protein co-chaperones of classes A and B, which synergistically boost HSP70-dependent disaggregation activity, providing a flexible further level of regulation for metazoan protein quality control, with direct relevance to human diseases such as age-related neurodegeneration. A novel protein quality control mechanism Microbes eliminate toxic intracellular protein aggregates thanks to HSP100 disaggregases, which are missing from animal cells. Now Bernd Bukau and colleagues have discovered an efficient protein disaggregation system in metazoan cells, which requires transient interactions between J-protein co-chaperones of classes A and B, which synergistically boost HSP70-dependent disaggregation activity. This system provides a flexible further level of regulation for metazoan protein quality control, with direct relevance to human diseases such as age-related neurodegeneration. Protein aggregates are the hallmark of stressed and ageing cells, and characterize several pathophysiological states 1 , 2 . Healthy metazoan cells effectively eliminate intracellular protein aggregates 3 , 4 , indicating that efficient disaggregation and/or degradation mechanisms exist. However, metazoans lack the key heat-shock protein disaggregase HSP100 of non-metazoan HSP70-dependent protein disaggregation systems 5 , 6 , and the human HSP70 system alone, even with the crucial HSP110 nucleotide exchange factor, has poor disaggregation activity in vitro 4 , 7 . This unresolved conundrum is central to protein quality control biology. Here we show that synergic cooperation between complexed J-protein co-chaperones of classes A and B unleashes highly efficient protein disaggregation activity in human and nematode HSP70 systems. Metazoan mixed-class J-protein complexes are transient, involve complementary charged regions conserved in the J-domains and carboxy-terminal domains of each J-protein class, and are flexible with respect to subunit composition. Complex formation allows J-proteins to initiate transient higher order chaperone structures involving HSP70 and interacting nucleotide exchange factors. A network of cooperative class A and B J-protein interactions therefore provides the metazoan HSP70 machinery with powerful, flexible, and finely regulatable disaggregase activity and a further level of regulation crucial for cellular protein quality control.