The structure of an Hsp90-immunophilin complex reveals cochaperone recognition of the client maturation state Graphical abstract Highlights d Structure of Hsp90:FKBP51:p23 reveals chaperone state for client maturation d FKBP51 specifically binds the closed, ATP state of Hsp90 via TPR domain contacts d The C-terminal helix extension of FKBP51 serves as an Hsp90 recognition element d Positioning FKBP51 PPIase domain adjacent to client binding may assist refolding

Cells are often exposed to physical or chemical stresses that can damage the structures of essential biomolecules. Stress-induced cellular damage can become deleterious if not managed appropriately. Rapid and adaptive responses to stresses are therefore crucial for cell survival. In eukaryotic cells, different stresses trigger post-translational modification of proteins with the small ubiquitin-like modifier SUMO. However, the specific regulatory roles of sumoylation in each stress response are not well understood. Here, we examined the sumoylation events that occur in budding yeast after exposure to hyperosmotic stress. We discovered by proteomic and biochemical analyses that hyperosmotic stress incurs the rapid and transient sumoylation of Cyc8 and Tup1, which together form a conserved transcription corepressor complex that regulates hundreds of genes. Gene expression and cell biological analyses revealed that sumoylation of each protein directs distinct outcomes. In particular, we discovered that Cyc8 sumoylation prevents the persistence of hyperosmotic stress-induced Cyc8-Tup1 inclusions, which involves a glutamine-rich prion domain in Cyc8. We propose that sumoylation protects against persistent inclusion formation during hyperosmotic stress, allowing optimal transcriptional function of the Cyc8-Tup1 complex.

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classes of co-chaperones compete for the EEVD motif in heat shock protein 70 (Hsp70) to tune its chaperone activities,