Abstract
Stress-specific activation of the chaperone Hsp33 requires the unfolding of a central linker region. This activation mechanism suggests an intriguing functional relationship between the chaperone's own partial unfolding and its ability to bind other partially folded client proteins. However, identifying where Hsp33 binds its clients has remained a major gap in our understanding of Hsp33's working mechanism. By using site-specific Fluorine-19 nuclear magnetic resonance experiments guided by in vivo crosslinking studies, we now reveal that the partial unfolding of Hsp33's linker region facilitates client binding to an amphipathic docking surface on Hsp33. Furthermore, our results provide experimental evidence for the direct involvement of conditionally disordered regions in unfolded protein binding. The observed structural similarities between Hsp33's own metastable linker region and client proteins present a possible model for how Hsp33 uses protein unfolding as a switch from self-recognition to high-affinity client binding.
Highlights
Stress-specific activation of the chaperone Hsp[33] requires the unfolding of a central linker region
Recent evidence suggested that the metastable regions, whose folding status is central to their activation process, do not constitute molecular gates that control accessibility to potentially hydrophobic client-binding sites[2,28,33], but participate in the binding of unfolding client proteins
In the case of conditionally disordered chaperone–client complexes, both chaperones and client proteins are at least partially unstructured, and the folding status of neither partner is well-defined in the bound state
Summary
Stress-specific activation of the chaperone Hsp[33] requires the unfolding of a central linker region. Upon exposure to specific protein-denaturing conditions, such as hypochlorous acid (HOCl) (for example, Hsp33)[1], low pH (for example, HdeA)[2] or elevated temperatures (for example, Hsp26)[12], the proteins rapidly undergo extensive unfolding and become active as chaperones These chaperones, appropriately termed conditionally disordered[11,13,14], exist in at least two distinct conformations—a folded inactive conformation and a partially unfolded active conformation1,2—making them ideal model systems for studying the role of protein disorder in chaperone function. Disulfide bonds form, zinc is released and the linker region unfolds This unfolding converts Hsp[33] into a high-affinity chaperone that preferentially binds to partially unfolded client proteins[15,16]. Structural similarities between Hsp33’s own metastable region and the client proteins explain how these chaperones use unfolding to switch from self-recognition to high-affinity client binding
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