Background: Many proteins are modified by lysine methylation. Results: It is shown that the previously uncharacterized enzyme METTL20 methylates electron transfer flavoprotein  (ETF), thereby inhibiting its ability to mediate electron transfer from acyl-CoA dehydrogenases. Conclusion: METTL20-mediated methylation modulates the function of ETF. Significance: The first mitochondrial lysine-specific protein methyltransferase in animals is reported, and the resulting methylation is shown to have functional consequences.
Human METTL20 is a mitochondrial, lysine-specific methyltransferase that methylates the -subunit of electron transfer flavoprotein (ETF). Interestingly, putative METTL20 orthologues are found in a subset of ␣-proteobacteria, including Agrobacterium tumefaciens. Using an activity-based approach, we identified in bacterial extracts two substrates of recombinant METTL20 from A. tumefaciens (AtMETTL20), namely ETF and the ribosomal protein RpL7/L12. We show that AtMETTL20, analogous to the human enzyme, methylates ETF on Lys-193 and Lys-196 both in vitro and in vivo. ETF plays a key role in mediating electron transfer from various dehydrogenases, and we found that its electron transferring ability was diminished by AtMETTL20-mediated methylation of ETF. Somewhat surprisingly, AtMETTL20 also catalyzed monomethylation of RpL7/L12 on Lys-86, a common modification also found in many bacteria that lack METTL20. Thus, we here identify AtMETTL20 as the first enzyme catalyzing RpL7/ L12 methylation. In summary, here we have identified and characterized a novel bacterial lysine-specific methyltransferase with unprecedented dual substrate specificity within the seven -strand class of lysine-specific methyltransferases, as it targets two apparently unrelated substrates, ETF and RpL7/L12. Moreover, the present work establishes METTL20-mediated methylation of ETF as the first lysine methylation event occurring in both bacteria and humans.
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