Abstract
The human protein arginine methyltransferase NDUFAF7 controls the assembly of the ∼1-MDa mitochondrial complex I (CI; the NADH ubiquinone oxidoreductase) by methylating its subunit NDUFS2. We determined crystal structures of MidA, the Dictyostelium ortholog of NDUFAF7. The MidA catalytic core domain resembles other eukaryotic methyltransferases. However, three large core loops assemble into a regulatory domain that is likely to control ligand selection. Binding of MidA to NDUFS2 is weakened by methylation, suggesting a mechanism for methylation-controlled substrate release. Structural and bioinformatic analyses support that MidA and NDUFAF7 and their role in CI assembly are conserved from bacteria to humans, implying that protein methylation already existed in proteobacteria. Invivo studies confirmed the critical role of the MidA methyltransferase activity for CI assembly, growth, and phototaxis of Dictyostelium. Collectively, our data elucidate the origin of protein arginine methylation and its use by MidA/NDUFAF7 to regulate CI assembly.
Highlights
Protein methylation is a reversible signaling process (Chang et al, 2007; Wesche et al, 2017) in which protein methyltransferases (PMTs) covalently modify proteins by attaching one or several methyl groups onto arginines or lysines (PRMTs and PKMTs, respectively) (Copeland, 2013; Copeland et al, 2009; Eram et al, 2016)
Studies of human and Dictyostelium discoideum complex I (CI) showed that the 400-kDa precursor assembly requires the catalytic activity of a PRMT called NADH dehydrogenase ubiquinone assembly factor 7 (NDUFAF7) in humans and mitochondrial dysfunction protein A (MidA) in D. discoideum (Carilla-Latorre et al, 2010; Rhein et al, 2013; Zurita Rendon et al, 2014)
These data suggested that MidA and NDUFAF7 contribute to CI pre-assembly by dimethylating NDUFS2 on Arg85, which interacts more strongly with the NDUFS7 subunit of CI
Summary
The biological role of protein arginine methyltransferases (PRMTs) outside of the nucleus is poorly understood. Hameed et al provide structural evidence for a proteobacterial origin of PRMTs. Their work suggests a methylationcontrolled substrate release mechanism and reveals that arginine methylation controls complex I assembly, growth, and phototaxis in Dictyostelium. Shahul Hameed et al, 2018, Cell Reports 24, 1996–2004 August 21, 2018 a 2018 The Authors.
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