000127902 001__ 127902 000127902 005__ 20241125101132.0 000127902 0247_ $$2doi$$a10.1002/pro.4723 000127902 0248_ $$2sideral$$a135014 000127902 037__ $$aART-2023-135014 000127902 041__ $$aeng 000127902 100__ $$aAraujo-Abad, Salomé 000127902 245__ $$aNew insights into cancer: MDM2 binds to the citrullinating enzyme PADI4 000127902 260__ $$c2023 000127902 5060_ $$aAccess copy available to the general public$$fUnrestricted 000127902 5203_ $$aPADI4 is one of the human isoforms of a family of enzymes implicated in the conversion of arginine to citrulline. MDM2 is an E3 ubiquitin ligase which is crucial for down-regulation of degradation of the tumor suppressor gene p53. Given the relationship between both PADI4 and MDM2 with p53-signaling pathways, we hypothesized they may interact directly, and this interaction could be relevant in the context of cancer. Here, we showed their association in the nucleus and cytosol in several cancer cell lines. Furthermore, binding was hampered in the presence of GSK484, an enzymatic PADI4 inhibitor, suggesting that MDM2 could bind to the active site of PADI4, as confirmed by in silico experiments. In vitro and in silico studies showed that the isolated N-terminal region of MDM2, N-MDM2, interacted with PADI4, and residues Thr26, Val28, Phe91 and Lys98 were more affected by the presence of the enzyme. Moreover, the dissociation constant between N-MDM2 and PADI4 was comparable to the IC50 of GSK484 from in cellulo experiments. The interaction between MDM2 and PADI4 might imply MDM2 citrullination, with potential therapeutic relevance for improving cancer treatment, due to the generation of new antigens. 000127902 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B25-20R$$9info:eu-repo/grantAgreement/ES/DGA/E45-20R$$9info:eu-repo/grantAgreement/ES/ISCIII/PI18-0394$$9info:eu-repo/grantAgreement/ES/MICINN/AEI/PID2021-127296OB-I00$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P 000127902 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/ 000127902 590__ $$a4.5$$b2023 000127902 592__ $$a4.419$$b2023 000127902 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b76 / 313 = 0.243$$c2023$$dQ1$$eT1 000127902 593__ $$aBiochemistry$$c2023$$dQ1 000127902 593__ $$aMolecular Biology$$c2023$$dQ1 000127902 593__ $$aMedicine (miscellaneous)$$c2023$$dQ1 000127902 594__ $$a12.4$$b2023 000127902 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000127902 700__ $$aRizzuti, Bruno 000127902 700__ $$aVillamarin-Ortiz, Adrián 000127902 700__ $$aPantoja-Uceda, David 000127902 700__ $$aMoreno-Gonzalez, Celia M. 000127902 700__ $$0(orcid)0000-0001-5664-1729$$aAbian, Olga$$uUniversidad de Zaragoza 000127902 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, Adrián$$uUniversidad de Zaragoza 000127902 700__ $$aNeira, José L. 000127902 700__ $$ade Juan Romero, Camino 000127902 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole. 000127902 773__ $$g32, 8 (2023), e4723 [21 pp.]$$pProtein sci.$$tProtein science$$x0961-8368 000127902 8564_ $$s7665030$$uhttps://zaguan.unizar.es/record/127902/files/texto_completo.pdf$$yVersión publicada 000127902 8564_ $$s2465119$$uhttps://zaguan.unizar.es/record/127902/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000127902 909CO $$ooai:zaguan.unizar.es:127902$$particulos$$pdriver 000127902 951__ $$a2024-11-22-11:59:25 000127902 980__ $$aARTICLE