Abstract
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 μ‐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.
Highlights
Smyd2 is a member of five lysine methyltransferases constituted by a suppressor of variegation, enhancer of zeste, trithorax (SET) domain (InterPro ID IPR001214), intercalated by a myeloid-nervy-DEAF1 (MYND) zinc binding domain (InterPro ID IPR002893)
In order to improve our understanding of the Smyd2 catalytic cycle, here we carried out l-second molecular dynamics (MD) simulations of the following systems: Smyd2 in complex with AdoMet cofactor (Model-A); Smyd2AdoMet-p53 peptide complex (ModelB); Smyd2-AdoHcy-p53 peptide complex (Model-C); and Smyd2-AdoMet in complex with the p53 peptide methylated at Lys372 (Model-D)
We report structural elements that describe the conformational rearrangements and flexibility of Smyd2 and p53 peptides; the global motion of Smyd2 protein associated in its binary and ternary states, and we highlight the dynamical characteristics of unmethylated and methylated p53 peptides as they bound to Smyd2
Summary
Smyd is a member of five lysine methyltransferases constituted by a suppressor of variegation, enhancer of zeste, trithorax (SET) domain (InterPro ID IPR001214), intercalated by a myeloid-nervy-DEAF1 (MYND) zinc binding domain (InterPro ID IPR002893). Recent proteomics studies have identified several additional potential Smyd substrates (Ahmed et al, 2016; Olsen et al, 2016) Another methyltransferase, Set, targets p53 (at Lys372) (Chuikov et al, 2004). We carried out a molecular dynamical study of Smyd, highlighting its differential substrate crevice characteristics as compared to Smyd (Chandramouli and Chillemi, 2016; Chandramouli et al, 2016). From these studies, a critical role of the Smyds C-terminal domain emerges that orchestrates the catalytic cycle. We have performed l-second molecular dynamics (MD) simulations to further understand the underlying molecular events regulating the Smyd catalytic cycle
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