Abstract
DNA methyltransferases (DNMTs) including DNMT1 are a conserved family of cytosine methylases that play crucial roles in epigenetic regulation. The versatile functions of DNMT1 rely on allosteric networks between its different interacting partners, emerging as novel therapeutic targets. In this work, based on the modeling structures of DNMT1-ubiquitylated H3 (H3Ub)/ubiquitin specific peptidase 7 (USP7) complexes, we have used a combination of elastic network models, molecular dynamics simulations, structural residue perturbation, network modeling, and pocket pathway analysis to examine their molecular mechanisms of allosteric regulation. The comparative intrinsic and conformational dynamics analysis of three DNMT1 systems has highlighted the pivotal role of the RFTS domain as the dynamics hub in both intra- and inter-molecular interactions. The site perturbation and network modeling approaches have revealed the different and more complex allosteric interaction landscape in both DNMT1 complexes, involving the events caused by mutational hotspots and post-translation modification sites through protein-protein interactions (PPIs). Furthermore, communication pathway analysis and pocket detection have provided new mechanistic insights into molecular mechanisms underlying quaternary structures of DNMT1 complexes, suggesting potential targeting pockets for PPI-based allosteric drug design.
Highlights
As an important member of DNA methyltransferases (DNMTs), DNMT1 is involved in many human diseases through aberrant DNA methylation, such as cancers and neurological disorders, representing a promising therapeutic target [1,2]
We aim to evaluate differences in dynamics and allosteric interactions of Apo-DNMT1 and the two binding protein complexes (DNMT1-H3Ub and DNMT1-ubiquitin specific peptidase 7 (USP7)), especially the intra- and inter-allosteric interactions landscape induced by interactors, mutations, and post-translational modifications (PTMs)
Based on structural modeling of full-length DNMT1 protein complexes, we have elucidated the molecular basis of the long-range allosteric activation of DNMT1-H3Ub and DNMT1USP7
Summary
As an important member of DNA methyltransferases (DNMTs), DNMT1 is involved in many human diseases through aberrant DNA methylation, such as cancers and neurological disorders, representing a promising therapeutic target [1,2]. The regulatory N-terminal platform includes the replication foci targeting sequence (RFTS) domain, a zinc-finger-like (CXXC) motif, two bromo-adjacent homology (BAH1 and BAH2) domains, and a flexible linker composed of lysine-glycine (KG) repeats [5]. For such a molecular machine, its biological functions depend on allosteric communication between the regulatory N-terminal regions and CD. We have explored only a minuscule fraction of their allosteric regulations
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