Pagliarini lab: An ancient kinase required for mitochondrial CoQ biosynthesis

Image of a new frontier in a widespread and ancient superfamily

Mitochondria are dynamic organelles whose functions are essential for nearly all human cells. Numerous human diseases, ranging from rare inborn errors in metabolism to common cancers, have been linked to mitochondrial dysfunction. However, our ability to treat these diseases is limited, in part because one-quarter of mitochondrial proteins have no established function.

Coenzyme Q (CoQ) biosynthesis provides an illustrative example of this problem. Although CoQ was discovered here at UW-Madison over 50 years ago, numerous gaps still exist in our understanding of how it is produced and how human diseases can affect its production. Work in the Pagliarini lab on mitochondrial proteins required for coenzyme Q biosynthesis is helping to close these gaps. One of these proteins is called ADCK3.

ADCK3 is a member of a largely uncharacterized kinase-like family, which is conserved across all superkingdoms of life. Jonathan Stefely, Andrew Reidenbach and coauthors recently discovered that ADCK3 adopts a highly atypical structure for a kinase (the main image shows a stylized map of the structure of ADCK3 in contrast to other structurally-defined protein kinase-like families).

Intriguingly, they found that these unique features of ADCK3’s structure inhibit protein kinase activity. Modifying these features enables the kinase to phosphorylate itself, but also compromises in vivo coenzyme Q biosynthesis. Ongoing work seeks to uncover the molecular mechanism by which the unique structural features of ADCK3 contribute to function. The ultimate goal of the Pagliarini lab is to understand how ADCK3 and other proteins work together to enable coenzyme Q biosynthesis and other essential mitochondrial functions.

Read the Molecular Cell article

Image of mitochondrial kinase

Photo By: Jonathan Stefely