Characterization of SETD3 methyltransferase–mediated protein methionine methylation

Dai, Shaobo; Holt, Matthew V.; Horton, John R.; Woodcock, Clayton B.; Patel, Anamika; Zhang, Xing; Young, Nicolas L.; Wilkinson, Alex W.; Cheng, Xiaodong

doi:10.1074/jbc.ra120.014072

Characterization of SETD3 methyltransferase–mediated protein methionine methylation

Journal Article · Fri Jun 05 00:00:00 EDT 2020 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.ra120.014072· OSTI ID:1669126

Dai, Shaobo ^[1]; Holt, Matthew V. ^[2]; Horton, John R. ^[1]; Woodcock, Clayton B. ^[1]; Patel, Anamika ^[3]; Zhang, Xing ^[1]; ^[2]; Wilkinson, Alex W. ^[4]; ^[1]

Univ. of Texas, Houston, TX (United States)
Baylor College of Medicine, Houston, TX (United States)
Emory Univ., Atlanta, GA (United States)
Stanford Univ., CA (United States)

Most characterized protein methylation events encompass arginine and lysine N-methylation, and only a few cases of protein methionine thiomethylation have been reported. Newly discovered oncohistone mutations include lysine-to-methionine substitutions at positions 27 and 36 of histone H3.3. In these cases, the methionine substitution localizes to the active-site pocket of the corresponding histone lysine methyltransferase, thereby inhibiting the respective transmethylation activity. SET domain–containing 3 (SETD3) is a protein (i.e. actin) histidine methyltransferase. Here, we generated an actin variant in which the histidine target of SETD3 was substituted with methionine. As for previously characterized histone SET domain proteins, the methionine substitution substantially (76-fold) increased binding affinity for SETD3 and inhibited SETD3 activity on histidine. Unexpectedly, SETD3 was active on the substituted methionine, generating S-methylmethionine in the context of actin peptide. The ternary structure of SETD3 in complex with the methionine-containing actin peptide at 1.9 Å resolution revealed that the hydrophobic thioether side chain is packed by the aromatic rings of Tyr³¹² and Trp²⁷³, as well as the hydrocarbon side chain of Ile³¹⁰. Our results suggest that placing methionine properly in the active site—within close proximity to and in line with the incoming methyl group of SAM—would allow some SET domain proteins to selectively methylate methionine in proteins.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE

OSTI ID:: 1669126

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 32 Vol. 295; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
S-adenosylmethionine (SAM)
SETD3
actin
enzyme catalysis
methionine
methionine methylation
methyltransferases S-methylmethionine
protein methylation
protein structure

Characterization of SETD3 methyltransferase–mediated protein methionine methylation

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References (56)

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