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Content Provider | World Health Organization (WHO)-Global Index Medicus |
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Author | Butler, James S. Loh, Stewart N. |
Description | Country affiliation: United States Author Affiliation: Butler JS ( Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.) |
Abstract | 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 degrees 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 degrees C to 35 degrees C. DBD therefore folds by the same two-channel mechanism at physiological temperature as it does at 10 degrees 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 degrees 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. |
ISSN | 09618368 |
e-ISSN | 1469896X |
Journal | Protein Science |
Issue Number | 11 |
Volume Number | 15 |
Language | English |
Publisher | Wiley-Blackwell (on behalf of The Protein Society) |
Publisher Date | 2006-11-01 |
Publisher Place | United States |
Access Restriction | Open |
Subject Keyword | Protein Folding Temperature Tumor Suppressor Protein P53 Chemistry Binding Sites Body Temperature Dna-binding Proteins Kinetics Models, Chemical Mutant Proteins Protein Denaturation Protein Structure, Tertiary Discipline Biochemistry |
Content Type | Text |
Resource Type | Article |
Subject | Biochemistry Molecular Biology Medicine |
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