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Activating a crucial enzyme spurs stimulated protein degradation
by Sarah Braner
A team of researchers has devised a method to activate protein degradation machinery in the cell. Credit: Shutterstock
If cellular protein degradation is like the garbage truck picking up the neighborhood trash, then a new approach takes the brakes off and speeds up trash collection.
Researchers led by Michael Rapé at the University of California, Berkeley, have developed a new strategy for what they call stimulated protein degradation, a cousin of targeted protein degradation (DOI: 10.1126/science.aed2525).
This approach doesn’t directly target E3 ligase, one of the most important cellular tools for degrading proteins, but instead one of the molecules that keeps E3 ligases in check. The researchers suspected that an agonist could dislodge that inhibitory molecule, thus activating the ligase and making it more effective at degrading faulty, disease-causing proteins.
The team tested this idea by focusing on an E3 ligase involved in degrading proteins that block access to the mitochondria. This ligase, CUL2FEM1B, is inhibited by brain-expressed X-linked (BEX) proteins. If this approach worked, a compound that detached those BEX proteins would let CUL2FEM1B degrade more mitochondria-blocking proteins. Experiments in induced pluripotent cell models showed that mitochondrial function was improved.
In a related perspective article, Ramanujan S. Hegde, a biochemist at the Medical Research Council Laboratory of Molecular Biology, says this approach may be useful for activating the E3 ligase Parkin to eliminate dysfunctional mitochondria and possibly help treat Parkinson’s disease.
Sarah Braner covers the life sciences from New York City.
From:C&en
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