Smyd2 conformational changes in response to p53 binding: role of the C‐terminal domain

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.

Histone methyltransferase SMYD2: ubiquitous regulator of disease

“…Similarly, p53 binds to a deep pocket of the interface between catalytic SET and CTD with an unprecedented U-shaped conformation, and the tetratrico-peptide repeat motif of the CTD and EDEE motif between the loop of anti-parallel β7 and β8 sheets of the SET core may play an important role in determining p53 substrate binding specificity [28]. Modeling study of SMYD2 in complex with a p53 peptide indicates that monomethylation of p53-Lys372 mediated by SET7/9 might result in steric conflict of the methyl group with the surrounding residues of SMYD2 to inhibit SMYD2-mediated methylation of p53-Lys370 [22, 29]. In addition, AZ505, a substrate-competitive inhibitor of SMYD2, binds in the peptide binding groove of SMYD2 to confine other substrates binding [21].…”

Pharmacological inhibition of SMYD2 protects against cisplatin-induced acute kidney injury in mice

“…This suggests that cisplatin-induced activation of SMYD2 may lead to p53 methylation and activation, and then triggers BAX activation and apoptosis. In this context, SMYD2 was reported to be able to induce its mono-methylation on lysine 370 residues ( Chandramouli et al, 2019 ), however, SMYD2 mono-methylation is repressive to p53-mediated transcriptional regulation and apoptosis, and p53 phosphorylation at serine 15 was not affected by SMYD2 ( Huang et al, 2006 ). These results are in contrast to our observations.…”

“…The underlying mechanism for these differences is unclear but may involve other post-translational modifications on p53 or demethylase-associated proteins. For example, SMYD2 may not only regulate p53 activity by direct methylation, but also indirectly regulate its activity by inducing expression of other methyltransferases or demethylases that regulate p53 methylation ( Chandramouli et al, 2019 ). In this regard, although SMYD2 is documented to be a monomethyl transferase, both K370me1 and K370me2 of p53 are detected in cells.…”

Unsupervised Learning Methods for Molecular Simulation Data

“…DBSCAN had been employed to find representative structures from MD simulations, , as well as to find regions characterized by different molecular densities, , in this case using molecules as data points. HDBSCAN has recently gained attention also in the analysis of MD trajectories, − mostly due to its capability to reveal hierarchical structures.…”