Abstract
Phosphatidylinositol 3-kinase-related kinases (PIKKs) are a family of kinases that control fundamentalprocesses, including cell growth, DNA damage repair, and gene expression. Although their regulation andactivities 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 specificallystabilizes PIKKs. Here, we describe a mechanism by which TTT promotes their de novo maturation in fissionyeast. We show that TTT recognizes newly synthesized PIKKs during translation. Although PIKKs form multimericcomplexes, we find that they do not engage in cotranslational assembly with their partners. Rather, ourfindings suggest a model by which TTT protects nascent PIKK polypeptides from misfolding and degradationbecause PIKKs acquire their native state after translation is terminated. Thus, PIKK maturation and assemblyare temporally segregated, suggesting that the biogenesis of large complexes requires both dedicated chaperonesand cotranslational interactions between subunits.