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

Gwendaline Lledo,Alberto Elías-Villalobos,Céline Faux,Ambre Noly,Damien Toullec,Martial Séveno,Dominique Helmlinger

doi:10.1016/j.celrep.2021.109867

Abstract

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.

Highlights

Most proteins function as part of multimeric complexes rather than in isolation
We recently showed that assembly of the Tra1/TRRAP subunit into the SAGA and NuA4/TIP60 transcription complexes requires a dedicated assembly factor, called the Triple T complex (TTT) (Detilleux et al, 2021; Elıas-Villalobos et al, 2019a)
In Saccharomyces cerevisiae and mammals, Tra1/ TRRAP is shared between the SAGA and the NuA4/TIP60 complexes

Summary

Introduction

Most proteins function as part of multimeric complexes rather than in isolation. These complexes adopt specific quaternary structures that are important for their functions, for example, enabling allosteric regulation. Various proteins can recognize the nascent polypeptide of their interacting partner in prokaryotes and eukaryotes, indicating a general phenomenon (Duncan and Mata, 2011; Shiber et al, 2018; Shieh et al, 2015) These mechanisms might be mutually exclusive, because subunits that do not engage cotranslationally require specific chaperones for their assembly (Shiber et al, 2018). Which features dictate whether a nascent polypeptide requires its partner or dedicated assembly factors for folding and maturation are not well understood. Whether both mechanisms cooperate to drive the biogenesis of certain complexes is unclear

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