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Published online before print September 25, 2006, 10.1110/ps.062324206
Protein Science (2006), 15:2457-2465. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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Folding and misfolding mechanisms of the p53 DNA binding domain at physiological temperature

James S. Butler and Stewart N. Loh

Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, USA

(RECEIVED May 2, 2006; FINAL REVISION July 14, 2006; ACCEPTED August 2, 2006)

p53 modulates a large number of cellular response pathways and is critical for the prevention of cancer. Wild-type p53, as well as tumorigenic mutants, exhibits the singular property of spontaneously losing DNA binding activity at 37°C. To understand the molecular basis for this effect, we examine the folding mechanism of the p53 DNA binding domain (DBD) at elevated temperatures. Folding kinetics do not change appreciably from 5°C to 35°C. DBD therefore folds by the same two-channel mechanism at physiological temperature as it does at 10°C. Unfolding rates, however, accelerate by 10,000-fold. Elevated temperatures thus dramatically increase the frequency of cycling between folded and unfolded states. The results suggest that function is lost because a fraction of molecules become trapped in misfolded conformations with each folding-unfolding cycle. In addition, at 37°C, the equilibrium stabilities of the off-pathway species are predicted to rival that of the native state, particularly in the case of destabilized mutants. We propose that it is the presence of these misfolded species, which can aggregate in vitro and may be degraded in the cell, that leads to p53 inactivation.

Keywords: cancer; mutation; aggregation; folding kinetics


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