How the enzymes that “tidy up” a cell are turned off and on

| Written by Jessica Moore
generic cell-related

When a cell has too much of a certain kind of machine or sensor, the extras are tagged for destruction. That tagging is carried out by enzymes that serve as the cell’s professional organizers, going through everything and deciding what’s not needed. These enzymes, called ubiquitin ligases because the tag they attach is named ubiquitin, are really important. If they don’t work right, cell parts that should be broken down instead hang around, or useful components are unnecessarily destroyed, which can cause major problems.

When ubiquitin ligases in a class called Nedd4 don’t work properly, they can contribute to diseases including Parkinson’s, epilepsy, inherited blood pressure disorders, and certain cancers. That’s because Nedd4 ligases regulate the amounts of cell components that control electrical activity in neurons, responses to brain chemicals and cell growth. To better understand Nedd4 ligases, a team of scientists including Dieter Wolf, M.D., professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), looked at how they’re turned off and on.

“We found that when Nedd4 ligases are turned off, they cluster together in groups of three,” says Wolf. “That happens because ubiquitin attaches to a certain part of the enzyme, moving it in a way that exposes another part that likes to stick to other Nedd4 ligases.”

Wolf and Khatereh Motamedchaboki, Ph.D., director of SBP’s proteomics core, did the proteomics analysis for the paper, published in the EMBO Journal. Those data were crucial for showing that ubiquitin is attached to the inactive form of Nedd4. The study was led by Gali Prag, Ph.D., a professor at Tel Aviv University.

“These results show that Nedd4 activity can be modulated—and that could open up a new approach to treating certain neurological disorders,” Wolf adds. “Once we understand more about these enzymes—for example, whether most Nedd4 ligases in a normal cell are in the active or the inactive form, and what the trigger is for ubiquitin to attach to Nedd4—we may be able to develop a new strategy for treating diseases linked to this enzyme, like Parkinson’s.”

The paper is available online here.

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