One of the key issues in biology is determining the mechanisms underlying the response of organisms to changes in their environment. It is known that ability of cells to sustain and recover after stress conditions depends on a well-developed and complex network of protein chaperones and co-chaperones. This proposal addresses fundamental questions in a recently discovered subgroup of molecular chaperones, intrinsically disordered chaperones, which use plasticity for their ATP-independent chaperone function.
Intrinsically disordered proteins (IDPs) are widespread and fulfill important functions associated with signaling and regulation. Although intrinsically disordered protein are considered to be a crucial part of the proteome, most experimental and computational studies have focused on the contribution of intrinsic disorder to signaling and assembly of multi-domain complexes, leaving molecular chaperones as an unexplored niche. The involvement of intrinsic plasticity in molecular recognition is usually explained by such terms as promiscuity and flexibility. Beyond these notions it still remains unclear why specific intrinsically disordered protein were selected to recognize signaling proteins, DNA, small ligands or aggregation-prone proteins. In this proposal, we aim to explore the putative links between intrinsically disordered regions (IDRs) and chaperone activity. In order to establish such links we propose to utilize innovative and multidisciplinary approach, which combines chaperone biochemistry, protein design, bioinformatics and state-of-the-art mass spectrometry to elucidate the central role of protein plasticity in maintaining protein homeostasis during stress conditions. This proposal will be based on the experiment-driven approach: computation will point the way, whereas experiments will navigate and optimize it. I am confident that this project can have a real impact, and will significantly alter the way the community thinks about chaperones and IDPs.
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