Proteobacterial Origin of Protein Arginine Methylation and Regulation of Complex I Assembly by MidA

Umar Shahul Hameed, Oana Sanislav, Sui T. Lay, Sarah J. Annesley, Chacko Jobichen, Paul R. Fisher, Kunchithapadam Swaminathan*, Stefan T. Arold

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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. In vivo 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. 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 methylation-controlled substrate release mechanism and reveals that arginine methylation controls complex I assembly, growth, and phototaxis in Dictyostelium.

Original languageEnglish (US)
Pages (from-to)1996-2004
Number of pages9
JournalCell reports
Issue number8
StatePublished - Aug 21 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors


  • SAXS
  • Seahorse respirometry
  • X-ray crystallography
  • complex I assembly
  • evolution
  • methylation
  • phototaxis
  • post-translational modification
  • proteobacteria

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


Dive into the research topics of 'Proteobacterial Origin of Protein Arginine Methylation and Regulation of Complex I Assembly by MidA'. Together they form a unique fingerprint.

Cite this