Human METTL20 methylates lysine residues adjacent to the recognition loop of the electron transfer flavoprotein in mitochondria.

TitleHuman METTL20 methylates lysine residues adjacent to the recognition loop of the electron transfer flavoprotein in mitochondria.
Publication TypeJournal Article
Year of Publication2014
AuthorsRhein, VF, Carroll, J, He, J, Ding, S, Fearnley, IM, Walker, JE
JournalJ Biol Chem
Volume289
Issue35
Pagination24640-51
Date Published2014 Aug 29
ISSN1083-351X
KeywordsAmino Acid Sequence, Base Sequence, Cell Line, Tumor, Chromatography, Affinity, DNA Primers, Electron Transport, Flavoproteins, Humans, Lysine, Mass Spectrometry, Methylation, Methyltransferases, Mitochondria, Molecular Sequence Data
Abstract

In mammalian mitochondria, protein methylation is a relatively uncommon post-transcriptional modification, and the extent of the mitochondrial protein methylome, the modifying methyltransferases, and their substrates have been little studied. As shown here, the β-subunit of the electron transfer flavoprotein (ETF) is one such methylated protein. The ETF is a heterodimer of α- and β-subunits. Lysine residues 199 and 202 of mature ETFβ are almost completely trimethylated in bovine heart mitochondria, whereas ETFα is not methylated. The enzyme responsible for the modifications was identified as methyltransferase-like protein 20 (METTL20). In human 143B cells, the methylation of ETFβ is less extensive and is diminished further by suppression of METTL20. Tagged METTL20 expressed in HEK293T cells specifically associates with the ETF and promotes the trimethylation of ETFβ lysine residues 199 and 202. ETF serves as a mobile electron carrier linking dehydrogenases involved in fatty acid oxidation and one-carbon metabolism to the membrane-associated ubiquinone pool. The methylated residues in ETFβ are immediately adjacent to a protein loop that recognizes and binds to the dehydrogenases. Suppression of trimethylation of ETFβ in mouse C2C12 cells oxidizing palmitate as an energy source reduced the consumption of oxygen by the cells. These experiments suggest that the oxidation of fatty acids in mitochondria and the passage of electrons via the ETF may be controlled by modulating the protein-protein interactions between the reduced dehydrogenases and the β-subunit of the ETF by trimethylation of lysine residues. METTL20 is the first lysine methyltransferase to be found to be associated with mitochondria.

DOI10.1074/jbc.M114.580464
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M114.580464
PubMed ID25023281
PubMed Central IDPMC4148887
Grant ListMC_U105663148 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom