Characterization of SETD3 methyltransferase-mediated protein methionine methylation.

Autor:	Dai S; Department of Epigenetics and Molecular Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA., Holt MV; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA., Horton JR; Department of Epigenetics and Molecular Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA., Woodcock CB; Department of Epigenetics and Molecular Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA., Patel A; Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA., Zhang X; Department of Epigenetics and Molecular Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA., Young NL; Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, USA., Wilkinson AW; Department of Biology, Stanford University, Stanford, California, USA alexw2@stanford.edu xcheng5@mdanderson.org., Cheng X; Department of Epigenetics and Molecular Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA alexw2@stanford.edu xcheng5@mdanderson.org.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Aug 07; Vol. 295 (32), pp. 10901-10910. Date of Electronic Publication: 2020 Jun 05.
DOI:	10.1074/jbc.RA120.014072
Abstrakt:	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 instances, 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 Tyr 312 and Trp 273 , as well as the hydrocarbon side chain of Ile 310 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. Competing Interests: Conflict of interest—The authors declare no competing interests with the contents of this article. (© 2020 Dai et al.)
Databáze:	MEDLINE
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