Abstract
BackgroundThe protein p53 plays an active role in the regulation of cell cycle. In about half of human cancers, the protein is inactivated by mutations located primarily in its DNA-binding domain. Interestingly, a number of these mutations possess temperature-induced DNA-binding characteristics. A striking example is the mutation of Arg248 into glutamine or tryptophan. These mutants are defective for binding to DNA at 310 K although they have been shown to bind specifically to several p53 response elements at sub-physiological temperatures (298–306 K).Methodology/Principal FindingsThis important experimental finding motivated us to examine the effects of temperature on the structure and configuration of R248Q mutant and compare it to the wild type protein. Our aim is to determine how and where structural changes of mutant variants take place due to temperature changes. To answer these questions, we compared the mutant to the wild-type proteins from two different aspects. First, we investigated the systems at the atomistic level through their DNA-binding affinity, hydrogen bond networks and spatial distribution of water molecules. Next, we assessed changes in their long-lived conformational motions at the coarse-grained level through the collective dynamics of their side-chain and backbone atoms separately.ConclusionsThe experimentally observed effect of temperature on the DNA-binding properties of p53 is reproduced. Analysis of atomistic and coarse-grained data reveal that changes in binding are determined by a few key residues and provide a rationale for the mutant-loss of binding at physiological temperatures. The findings can potentially enable a rescue strategy for the mutant structure.
Highlights
P53 is the most mutated protein in human cancers,[1] and mutations of p53 alone account for more than half of invasive types of cancer.[2]
Analysis of atomistic and coarse-grained data reveal that changes in binding are determined by a few key residues and provide a rationale for the mutant-loss of binding at physiological temperatures
According to the latest version (R15) of the TP53 mutation database,[3] 27 580 different somatic mutations have been identified in the full-length protein and the overwhelming majority of alterations are located within the core DNAbinding domain (DBD)
Summary
P53 is the most mutated protein in human cancers,[1] and mutations of p53 alone account for more than half of invasive types of cancer.[2]. Contact mutants are characterized by the direct loss of the sequence–specific transactivation activity while retaining the wildtype (WT) conformation.[5] Structural mutations, on the other hand, involve residues primarily responsible for maintaining the conformational integrity of the DBD and stabilizing the p53 DNA–binding surface. Such alterations generate local structural defects, which in turn transfer to critical regions of the DBD, causing indirect loss of DNA binding.[6] Failure to bind DNA prevents p53-dependent transcription and inhibits p53mediated tumor suppression. These mutants are defective for binding to DNA at 310 K they have been shown to bind to several p53 response elements at sub-physiological temperatures (298–306 K)
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