The Hsp90 cochaperone TTT promotes cotranslational maturation of PIKKs prior to complex assembly

Phosphatidylinositol 3-kinase-related kinases (PIKKs) are a family of kinases that control fundamental processes, including cell growth, DNA damage repair, and gene expression. Although their regulation and activities are well characterized, little is known about how PIKKs fold and assemble into active complexes. Previous work has identified a heat shock protein 90 (Hsp90) cochaperone, the TTT complex, that specifically stabilizes PIKKs. Here, we describe a mechanism by which TTT promotes their de novo maturation in fission yeast. We show that TTT recognizes newly synthesized PIKKs during translation. Although PIKKs form multimeric complexes, we find that they do not engage in cotranslational assembly with their partners. Rather, our findings suggest a model by which TTT protects nascent PIKK polypeptides from misfolding and degradation because PIKKs acquire their native state after translation is terminated. Thus, PIKK maturation and assembly are temporally segregated, suggesting that the biogenesis of large complexes requires both dedicated chaperones and cotranslational interactions between subunits.

Automated summary

PIKKs, a family of kinases controlling fundamental cellular processes, are stabilized by the Hsp90 cochaperone TTT complex during their de novo maturation in fission yeast. TTT recognizes and protects nascent PIKKs during translation, indicating a model where PIKKs acquire their native state after translation, separate from cotranslational assembly with their partners. This highlights the importance of dedicated chaperones and interactions between subunits in the biogenesis of large complexes.