Drebrin (red) and F-actin (green) convene at the tip of a neuron that is just beginning to grow.

Drebrin (red) and F-actin (green) convene at the tip of a neuron that is just beginning to grow.

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Worth et al. reveal that the protein drebrin, which is crucial for neuron development and memory, controls its own activity by folding over on itself.

Drebrin bolsters the dentritic spines that store memories, and it vanishes from these spines in people who have Alzheimer’s disease and other memory-robbing conditions. During development, drebrin performs other tasks, promoting the extension of neurites and helping direct growing neurons in the right direction. At the elongating tip of a neuron, drebrin links microtubules to actin filaments, thus possibly strengthening the tip and ensuring the delivery of necessary materials. Drebrin can also drive the formation of F-actin bundles, which brace cellular extensions. But researchers don’t understand how the protein interacts with actin.

Worth et al. investigated the interaction by running a computer analysis of drebrin’s amino acid sequence, which revealed five domains in the molecule. The researchers engineered kidney cells to manufacture drebrin variants that were missing different sections and then tested the molecules’ abilities to latch onto actin and spur filopodia to sprout, a sign that they could bundle actin. The team found that two domains—a coiled-coil domain and a helical domain—worked together to bundle actin. However, in vitro experiments on recombinant drebrin made by bacteria found that it was a feeble actin bundler.

The explanation for this apparent contradiction, Worth et al. discovered, is that drebrin inhibits itself. The molecule doubles over when two of the non–actin-binding domains interconnect, obstructing the coiled-coil domain. Cells can remove this inhibition by enlisting the protein Cdk5, which affixes a phosphate group near the coiled-coil domain and exposes the domain to actin. Local activation of Cdk5 could couple microtubules to F-actin at a specific site and spur growth in that direction.

et al
J. Cell Biol.

Author notes

Text by Mitch Leslie