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Allosteric interactions by p53 mRNA govern HDM2 E3 ubiquitin ligase specificity under different conditions
Ataxia Telangiectasia Mutated Proteins; ATM protein, human; MDM2 protein, human; MDM4 protein, human; Nuclear Proteins; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; RNA, Messenger; TP53 protein, human; Tumor Suppressor Protein p53
messenger RNA; protein HDMX; protein MDM2; protein p53; ubiquitin protein ligase E3; unclassified drug; zinc finger protein; ATM protein; ATM protein, human; MDM2 protein, human; MDM4 protein, human; messenger RNA; nuclear protein; oncoprotein; protein MDM2; protein p53; TP53 protein, human; allosterism; Article; circular dichroism; controlled study; DNA damage; enzyme specificity; human; nonhuman; priority journal; protein conformation; protein degradation; protein modification; protein phosphorylation; protein processing; protein protein interaction; protein purification; RING finger motif; ubiquitination; zinc finger motif; allosterism; animal; chemistry; enzyme specificity; genetics; metabolism; phosphorylation; protein domain; protein unfolding; Allosteric Regulation; Animals; Ataxia Telangiectasia Mutated Proteins; Humans; Nuclear Proteins; Phosphorylation; Protein Domains; Protein Unfolding; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; RNA, Messenger; Substrate Specificity; Tumor Suppressor Protein p53
HDM2 and HDMX are key negative regulatory factors of the p53 tumor suppressor under normal conditions by promoting its degradation or preventing its trans activity, respectively. It has more recently been shown that both proteins can also act as positive regulators of p53 afterDNAdamage. This involves phosphorylation byATMon serine residues HDM2(S395) and HDMX(S403), promoting their respective interaction with the p53 mRNA. However, the underlying molecular mechanisms of how these phosphorylation events switch HDM2 and HDMX from negative to positive regulators of p53 is not known. Our results show that these phosphorylation events reside within intrinsically disordered domains and change the conformation of the proteins. The modifications promote the exposition of N-terminal interfaces that support the formation of a new HDMX-HDM2 heterodimer independent of the C-terminal RING-RING interaction. The E3 ubiquitin ligase activity of this complex toward p53 is prevented by the p53 mRNA ligand but, interestingly, does not affect the capacity to ubiquitinate HDMX and HDM2. These results show how ATM-mediated modifications of HDMX and HDM2 switch HDM2 E3 ubiquitin ligase activity away from p53 but toward HDMX and itself and illustrate how the substrate specificity of HDM2 E3 ligase activity is regulated. © 2016, American Society for Microbiology.
Consejo Nacional de Ciencia y Tecnología, CONACYT: 327879
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