Chaperone binding to tumor suppressor is reportedly heterogeneous and transient.
Researchers have turned current thinking on its head with the finding that the tumor suppressor protein p53 becomes loose and less structured, rather than conformationally tightened, when complexed with the chaperone protein Hsp90. The Scripps Research Institute scientists who report the discovery claim that their results provide the first structural insights into the shape of a client protein in the presence of its chaperone and suggest that proteins can be active in an unfolded state as well as when they take on a specific conformation. Their findings are reported in Nature Structural & Molecular Biology in a paper titled, “The client protein p53 adopts a molten globule-like state in the presence of Hsp90.”
The Scripps team used protein NMR spectroscopy to analyze the shape of Hsp90 constructs interacting with the tumor suppressor p53. Although many researchers have studied the interactions of Hsp90 and its client proteins, none of the studies have been able to determine either what the client protein looked like in the complex or what part of Hsp90 was in contact with the client, remarks lead Scripps investigator, H. Jane Dyson, Ph.D. “It was a real surprise to find that, when bound to Hsp90, p53 is loosened and becomes less ordered, forming a molten globule-like state,” Dr. Dyson notes. “This contradicts what everyone thought of as the function of chaperone proteins—to help other proteins fold into a well-defined three-dimensional structure. Our study demonstrates that the interaction is surprisingly nonspecific, and that rather than making a distinct complex, the Hsp90 causes a change in the overall structure of the client.”
The researchers suggest that the basic underlying interaction of Hsp90 with its client proteins is heterogeneous and transient and gives the potential for manifold chaperone-client complexes that could be modified and tuned to various tasks, depending on the presence of ATP and specific co-chaperones. In the case of p53, these interactions lead to the loosening of the structure of the protein into a state resembling a molten globule.
If the current observation proves general, it has notable implications for the understanding of Hsp90 function, they add, as a general propensity of Hsp90 to cause loosening of the structures of its client proteins would be consistent with several of its known functions.
“We are realizing that proteins are a lot more versatile than we understood in the past,” Dr. Dyson concludes. “This is just the beginning of understanding how these important, and very common, chaperone proteins are functioning.”