1. Home
  2. Seminars
  3. The role of Selenoprotein O in...

The role of Selenoprotein O in mitochondrial signaling

The role of Selenoprotein O in mitochondrial signaling

Abstract: Protein AMPylation, the covalent addition of adenosine monophosphate (AMP) to protein substrates, has been known as a post translational modification for over 50 years.

Relative to PTMs such as phosphorylation, the breadth of protein AMPylation is underexplored. To address this gap, we developed an enrichment technique to isolate and study AMPylated proteins using a nucleotide-binding protein, hinT. Using cryo-EM guided mutagenesis, we optimized enrichment to identify novel substrates of the mitochondrial AMPylase, Selenoprotein O. We show that mammalian Selenoprotein O regulates metabolic flux through AMPylation of key mitochondrial proteins including glutamate dehydrogenase and pyruvate dehydrogenase.

Our findings highlight the broader significance of AMPylation, an emerging post translational modification with critical roles in signal transduction and disease pathology. Remarkably, Selenoprotein O-mediated AMPylation is conserved in bacteria and humans, yet the enzyme that removes the AMP from modified proteins remains unknown.

Using our newly developed enrichment platform, we identified that the ribonuclease, RNase Z, is both necessary and sufficient to catalyze deAMPylation of AMPylated substrates. These results establish RNase Z as a moonlighting enzyme with previously unrecognized functional roles beyond tRNA processing, expanding our understanding of its biological significance. Identification of an evolutionarily conserved deAMPylase highlights the importance of reversible AMPylation as a biological regulatory mechanism, akin to well-studied post translational modifications such as protein phosphorylation.

Together, our discovery of the mitochondrial deAMPylase and our novel enrichment strategy lay the foundation for defining the role of AMPylation in cellular signaling and highlight the central role of Selenoprotein O in mitochondrial biology.

Add to your calendar or Include in your list