Abstract
Lysine-specific demethylase 1 (LSD1), the first identified histone demethylase, is a flavin-dependent amine oxidase which specifically demethylates mono- or dimethylated H3K4 and H3K9 via a redox process. It participates in a broad spectrum of biological processes and is of high importance in cell proliferation, adipogenesis, spermatogenesis, chromosome segregation and embryonic development. To date, as a potential drug target for discovering anti-tumor drugs, the medical significance of LSD1 has been greatly appreciated. However, the catalytic mechanism for the rate-limiting reductive half-reaction in demethylation remains controversial. By employing a combined computational approach including molecular modeling, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, the catalytic mechanism of dimethylated H3K4 demethylation by LSD1 was characterized in details. The three-dimensional (3D) model of the complex was composed of LSD1, CoREST, and histone substrate. A 30-ns MD simulation of the model highlights the pivotal role of the conserved Tyr761 and lysine-water-flavin motif in properly orienting flavin adenine dinucleotide (FAD) with respect to substrate. The synergy of the two factors effectively stabilizes the catalytic environment and facilitated the demethylation reaction. On the basis of the reasonable consistence between simulation results and available mutagenesis data, QM/MM strategy was further employed to probe the catalytic mechanism of the reductive half-reaction in demethylation. The characteristics of the demethylation pathway determined by the potential energy surface and charge distribution analysis indicates that this reaction belongs to the direct hydride transfer mechanism. Our study provides insights into the LSD1 mechanism of reductive half-reaction in demethylation and has important implications for the discovery of regulators against LSD1 enzymes.
Highlights
Histones are subjected to a variety of post-translational modifications, including acetylation, phosphorylation, ubiquitination, sumolation and methylation [1,2]
Similar results were obtained in recent studies of the catalytic mechanism of maize polyamine oxidase (MPAO) [57] and mammalian polyamine oxidase [58], two homologues of lysine-specific demethylase 1 (LSD1), which demonstrated the corresponding conserved lysines in active center were deprotoned upon substrate binding from both experimental and theoretical perspectives [57,58,59]
These results suggest that the neutral state of dimethylated H3K4 was the dominating form under physiological environment because the two methyl groups would slightly enhance the hydrophobicity of the microenvironment and trigger more effective electrostatic effect acted on the protonation states
Summary
Histones are subjected to a variety of post-translational modifications, including acetylation, phosphorylation, ubiquitination, sumolation and methylation [1,2]. These modifications steadily modulate chromatin structure and the consequent diverse chromatin-based processes in a combined fashion. The recent discovery of lysine-specific demethylase 1 (LSD1) and Jumonji domain-containing proteins strongly challenged this dogma, by demonstrating that histone lysine methylation can be actively and dynamically regulated by histone methylase and demethylase [3]. The expression of LSD1 is closely correlated with the relapse of prostate cancer during therapy [23,24]
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