Small heat-shock proteins (sHSPs) are important members of the cellular stress response in all species. Their best-described function is the binding of early unfolding states and the resulting prevention of protein aggregation. Many sHSPs exist as a polydisperse composition of oligomers, which undergoes changes in subunit composition, folding status, and relative distribution upon heat activation. To date, only an incomplete picture of the mechanism of sHSP activation exists; in particular, the molecular basis of how sHSPs bind client proteins and mediate client specificity is not fully understood. In this study, we have applied cross-linking mass spectrometry (XL-MS) to obtain detailed structural information on sHSP activation and client binding for yeast Hsp26. Our cross-linking data reveals the middle domain of Hsp26 as a client-independent interface in multiple Hsp26::client complexes and indicates that client specificity is likely mediated via additional binding sites within its α-crystallin domain and C-terminal extension. Our quantitative XL-MS data underpins the middle domain as the main driver of heat-induced activation and client binding but shows that global rearrangements spanning all domains of Hsp26 take place simultaneously. We also investigated a Hsp26::client complex in the presence of Ssa1 (Hsp70) and Ydj1(Hsp40) at the initial stage of refolding and observe that the interaction between refolding chaperones is altered by the presence of a client protein, pointing to a mechanism where the interaction of Ydj1 with the HSP::client complex initiates the assembly of the active refolding machinery.
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