Mechanism of DNA-binding loss upon single-point mutation in p53.

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dc.contributor.authorWright, Jon Den_US
dc.contributor.authorLim, Carmayen_US
dc.date.accessioned2007-08-05en_US
dc.date.accessioned2009-06-01T15:03:42Z
dc.date.available2007-08-05en_US
dc.date.available2009-06-01T15:03:42Z
dc.date.issued2007-08-05en_US
dc.description.abstractOver 50% of all human cancers involve p53 mutations,which occur mostly in the sequence-specific DNA-binding central domain (p53c), yielding little/non-detectable af?nity to the DNA consensus site.Despite our current understanding of protein-DNA recognition,the mechanism(s) underlying the loss in protein-DNA binding afnity/ specificity upon single-point mutation are not well understood. Our goal is to identify the common factors governing the DNA-binding loss of p53c upon substitution of Arg 273 to His or Cys,which are abundant in human tumours. By computing the free energies of wild-type and mutant p53c binding to DNA and decomposing them into contributions from individual residues, the DNA-binding loss upon charge/noncharge -conserving mutation of Arg 273 was attributed not only to the loss of DNA phosphate contacts, but also to longer-range structural changes caused by the loss of the Asp 281 salt-bridge. The results herein and in previous works suggest that Asp 281 plays a critical role in the sequence-specific DNA-binding function of p53c by (i)orienting Arg 273 and Arg 280 in an optimal position to interact with the phosphate and base groups of the consensus DNA, respectively, and (ii) helping to maintain the proper DNA-binding protein conformation.en_US
dc.description.affiliationInstitute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, ROC.en_US
dc.identifier.citationWright JD, Lim C. Mechanism of DNA-binding loss upon single-point mutation in p53. Journal of Biosciences. 2007 Aug; 32(5): 827-39en_US
dc.identifier.urihttps://imsear.searo.who.int/handle/123456789/111274
dc.language.isoengen_US
dc.source.urihttps://www.ias.ac.in/jbiosci/index.htmlen_US
dc.subject.meshAmino Acid Substitution --geneticsen_US
dc.subject.meshArginine --geneticsen_US
dc.subject.meshBinding Sites --geneticsen_US
dc.subject.meshCysteine --geneticsen_US
dc.subject.meshDNA --geneticsen_US
dc.subject.meshHumansen_US
dc.subject.meshPoint Mutationen_US
dc.subject.meshProtein Binding --geneticsen_US
dc.subject.meshThermodynamicsen_US
dc.subject.meshTumor Suppressor Protein p53 --geneticsen_US
dc.titleMechanism of DNA-binding loss upon single-point mutation in p53.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.typeValidation Studiesen_US
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