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bioRxiv · 10.1101/476705

Structural insights into SETD3-mediated histidine methylation on β-actin

Guo, Q.·Liao, S.·Tomaka, W.·Kwiatkowski, S.·Wu, G.·Drozak, J.·Min, J.·Xu, C.
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Abstract

SETD3 is a member of SET (Su(var)3-9, Enhancer of zeste, and Trithorax) domain protein superfamily and plays important roles in hypoxic pulmonary hypertension, muscle differentiation, and carcinogenesis. In a previous paper (Kwiatkowski et al. 2018), we have identified SETD3 as the actin-specific methyltransferase that methylates the N3 of His73 on {beta}-actin. Here we present two structures of S-adenosyl-L-homocysteine-bound SETD3 in complex with either an unmodified {beta}-actin peptide or its His-methylated variant. Structural analyses supported by the site-directed mutagenesis experiments and the enzyme activity assays indicated that the recognition and methylation of {beta}-actin by SETD3 is highly sequence specific, and both SETD3 and {beta}-actin adopt pronounce conformational changes upon binding to each other. In conclusion, the structural research uncovers the molecular mechanism of sequence-selective histidine methylation by SETD3, which not only throws light on protein histidine methylation phenomenon, but also facilitates the design of small molecule inhibitors of SETD3.

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Guo, Q., Liao, S., Tomaka, W., Kwiatkowski, S., Wu, G., Drozak, J., Min, J., Xu, C.. 2018-11-26. Structural insights into SETD3-mediated histidine methylation on β-actin. https://doi.org/10.1101/476705

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