title: Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions.
abstract: 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 after DNA damage. This involves phosphorylation by ATM on 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.
authors.affiliation: Laboratorio de Interacciones Biomoleculares y Cáncer, Instituto de Física, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México.
authors.forename: Ixaura
authors.initials: I
authors.lastname: Medina-Medina
authors.affiliation: Laboratorio de Interacciones Biomoleculares y Cáncer, Instituto de Física, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México.
authors.forename: Paola
authors.initials: P
authors.lastname: García-Beltrán
authors.affiliation: Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaria de Salud, Distrito Federal, Mexico City, México.
authors.forename: Ignacio
authors.initials: I
authors.lastname: de la Mora-de la Mora
authors.affiliation: Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaria de Salud, Distrito Federal, Mexico City, México.
authors.forename: Jesús
authors.initials: J
authors.lastname: Oria-Hernández
authors.affiliation: Équipe Labellisée Ligue contre le Cancer, INSERM UMRS1162, Institut de Génétique Moléculaire, Université Paris 7, Hôpital Saint Louis, Paris, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Millot
authors.affiliation: Équipe Labellisée Ligue contre le Cancer, INSERM UMRS1162, Institut de Génétique Moléculaire, Université Paris 7, Hôpital Saint Louis, Paris, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Fahraeus
authors.affiliation: Laboratorio de Bioquímica-Genética, Instituto Nacional de Pediatría, Secretaria de Salud, Distrito Federal, Mexico City, México.
authors.forename: Horacio
authors.initials: H
authors.lastname: Reyes-Vivas
authors.affiliation: Laboratorio de Interacciones Biomoleculares y Cáncer, Instituto de Física, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México.
authors.forename: José G
authors.initials: JG
authors.lastname: Sampedro
authors.affiliation: Laboratorio de Interacciones Biomoleculares y Cáncer, Instituto de Física, Universidad Autónoma de San Luis Potosí, San Luis Potosí, México vanesa@ifisica.uaslp.mx.
authors.forename: Vanesa
authors.identifier: 0000-0001-6949-5986
authors.initials: V
authors.lastname: Olivares-Illana
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D006801:Humans; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D000072417:Protein Domains; D058767:Protein Unfolding; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013379:Substrate Specificity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins