Study reports structural and molecular determinant(s) of target specificity of actin histidine vs. lysine in the active site of SETD3. To facilitate the methyl transfer reaction SETD3 provides a local environment that promotes deprotonation of the target nitrogen N3 of histidine (and concomitant protonation of N1).
Structural analyses supported by biochemical experiments and enzyme activity assays indicate that the recognition and methylation of beta-actin by SETD3 are highly sequence specific and that both SETD3 and beta-actin adopt pronounced conformational changes upon binding to each other
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