期刊
MOLECULAR ONCOLOGY
卷 13, 期 6, 页码 1450-1461出版社
WILEY
DOI: 10.1002/1878-0261.12502
关键词
AdoMet; C-terminal domain; lysine methylation; molecular dynamics; p53; Smyd2
类别
资金
- 'Departments of Excellence-2018' Program (Dipartimenti di Eccellenza) of the Italian Ministry of Education, University and Research, DIBAF-Department of University of Tuscia, Project 'Landscape 4.0 - food, wellbeing and environment'
- Medical Research Council
- Associazione Italiana per la Ricerca contro il Cancro (AIRC) [20473]
- Regione Lazio through LazioInnova Progetto Gruppo di Ricerca [85-2017-14986]
- MRC [MC_U132670600, MC_UU_00025/2] Funding Source: UKRI
Smyd2 lysine methyltransferase regulates monomethylation of histone and nonhistone lysine residues using S-adenosylmethionine cofactor as the methyl donor. The nonhistone interactors include several tumorigenic targets, including p53. Understanding this interaction would allow the structural principles that underpin Smyd2-mediated p53 methylation to be elucidated. Here, we performed mu-second molecular dynamics (MD) simulations on binary Smyd2-cofactor and ternary Smyd2-cofactor-p53 peptide complexes. We considered both unmethylated and monomethylated p53 peptides (at Lys370 and Lys372). The results indicate that (a) the degree of conformational freedom of the C-terminal domain of Smyd2 is restricted by the presence of the p53 peptide substrate, (b) the Smyd2 C-terminal domain shows distinct dynamic properties when interacting with unmethylated and methylated p53 peptides, and (c) Lys372 methylation confines the p53 peptide conformation, with detectable influence on Lys370 accessibility to the cofactor. These MD results are therefore of relevance for studying the biology of p53 in cancer progression.
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