Abstract
The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new insights into the deprotonation process and the role of the catalytic machinery in the methyl-transfer reaction. Our finding suggests that the source of the activation mechanism comes from conformational restriction mediated by the formation of a network of salt-bridges between MLL3 and one of the activating subunits, which restricts and stabilizes the positioning of several residues relevant for the catalysis. New insights into the deprotonation mechanism of lysine are provided, identifying a valine residue as crucial in the positioning of the water molecule in charge of the process. Finally, a tyrosine residue was found to assist the methyl transfer from SAM to the target lysine.
Highlights
Epigenetic writing such as the methylation of the histone tail is an emerging focus of research because of its involvement in important post-translational processes
The mixed lineage leukemia (MLL) family of proteins corresponds to a set of non-redundant methyltransferases found in humans, from which the deregulation of MLL3 functioning has been detected in several types of tumors, such as breast cancer, gastric cancer, medulloblastoma, non-Hodgkin lymphoma, among several others [2,3,4,5,6,7,8]
MLL3 is a mono-methyltransferase that targets lysine 4 (Lys4) from histone 3 (H3K4), an epigenetic mark that has been related to enhancer elements involved in the activation of tumor suppressor genes, its inactivation affects the protective mechanism against tumor development [9,10]
Summary
Epigenetic writing such as the methylation of the histone tail is an emerging focus of research because of its involvement in important post-translational processes. Its deregulation has been related to aberrant gene regulation leading to several diseases such as cancer [1]. Methyltransferases target a lysine or an arginine residue from the. These residues can be mono-, di- and trimethylated with the epigenetic outcome depending on the product multiplicity. MLL3 is a mono-methyltransferase that targets lysine 4 (Lys4) from histone 3 (H3K4), an epigenetic mark that has been related to enhancer elements involved in the activation of tumor suppressor genes, its inactivation affects the protective mechanism against tumor development [9,10]
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