Smart molecular glue positions nuclei correctly for cell division

Researchers at the Paul Scherrer Institute PSI and ETH Zurich have discovered how proteins in cells can form tiny droplets that act as smart molecular glue. The glue they discovered attaches to the ends of filaments called microtubules and ensures that the nuclei are correctly positioned for cell division.Findings published in nature cell biologyexplaining the long-standing mystery of how the moving protein structures of cellular machinery are coupled.

Couplings are important for machines with moving parts. Whether rigid or flexible, connections between motor shafts or body joints, the material properties allow mechanical forces to be transmitted as needed. Nowhere is it more optimized than in the cell, where interactions between migrating subcellular structures support many biological processes. But how nature forms this bond has long baffled scientists.

Researchers are now investigating a coupling that is important for yeast cell division, and have shown that to do this, proteins cooperate to condense into droplets. This research was a collaboration between the team of Michel Steinmetz of the Paul Scherrer Institute PSI and Yves Barral of ETH Zurich, with the help of the group of Eric Dufresne and Jörg Stelling of ETH Zurich.

By forming droplets, proteins achieve perfect material properties to ensure their biological function. The discovery is just the beginning of a new understanding of the role smart liquids play in cells, believes Barral, whose research group is investigating the process of cell division in yeast. “We find that liquids composed of biomolecules are very sophisticated and can exhibit a much broader range of properties than they could from a macroscopic point of view. , I think you’ll find that these liquids have impressive properties: they’ve been chosen by hundreds of millions of years of evolution.”

Microtubules: Toropes of Cells

The study focuses on the coupling that occurs at the ends of microtubules (filaments that criss-cross the cell’s cytoplasm), which look a lot like alien tentacles. These hollow tubes are formed from their constituent tubulin and act as traction ropes, transporting various cargoes throughout the cell.

Microtubules receive one of the most important cargoes during cell division. In yeast, it has the important task of dragging the nucleus containing the dividing chromosomes between the mother cell and the budding daughter cell. To do this, the microtubules must connect, via motor proteins, to actin cables anchored in the plasma membrane of the emerging daughter cell. It draws microtubules into daughter cells until the cargo of substances reaches the desired destination between the two cells.

Essential for the progression of cell division, this coupling is required to allow motor proteins to withstand the tension of walking and to delicately manipulate the nucleus. Michel Steinmetz, an expert in the structural biology of microtubules in his PSI research group, explains: There is no genetic material that cannot survive. ”

Flexible coupling in nature

In yeast, three proteins that form the core of the so-called Kar9 network decorate the tips of microtubules to achieve this binding. How they achieve the required material properties seemed to contradict the conventional understanding of protein interactions.

One question that has long intrigued scientists is how the three core Kar9 network proteins remain attached to the tips of microtubules even when tubulin subunits are added or removed. That’s what I meant. Equivalent to the hook at the end of the towline remaining in place while the adjacent section of rope is inserted. or cut out. Here, their findings provide an answer: Much like a drop of liquid glue sticks to the end of a pencil, this protein ‘liquid’ can stick to the ends of microtubules as they grow or shrink. .

The researchers found that three core Kar9 network proteins cooperate through a web of weak interactions to achieve this liquid property. Proteins interact in many different ways, so if one interaction fails, others remain, and much of the ‘glue’ persists. The researchers believe that this gives the microtubules the necessary flexibility to remain attached to the motor protein under tension.

To make their findings, the researchers systematically examined the interactions between the three protein components of the Kar9 network. was mutated to selectively remove the interaction site and the effect could be observed. live When in vitro.

in solution, The three proteins came together to form different droplets like oil in water. To prove that this is happening in yeast cells, researchers investigated the effects of mutations on cell division and the protein’s ability to track the ends of contracting microtubules.

“It was fairly easy to prove that proteins interact to form liquid condensates. in vitroBut providing convincing evidence that this is happening has been a big challenge. liveit took several years,” explains Steinmetz, who first postulated the idea of ​​a “liquid protein glue” for microtubule tip-binding proteins with his Dutch colleagues in a 2015 review publication. .

Not your bog standard multi-purpose glue

Barral was impressed with how sophisticated the glue was. “It’s not just a glue, it’s a smart glue that can integrate spatial information and form only in the right place.” Among the complex tangles of identical microtubules in the cytoplasm, only one microtubule is soluble. It can receive droplets and attach to actin cables to pull genetic information into place. “It’s mind-boggling how nature can assemble complex structures at the ends of just one microtubule and not on others,” he emphasizes.

Researchers believe that the liquid properties of proteins play an important role in achieving this specificity. They first form small droplets on many microtubules and then somehow converge to form one large oil droplet on a single microtubule, much like the tiny oil droplets in a vinaigrette fuse together. It is assumed to form droplets. Exactly how this is achieved remains a mystery and is the subject of investigation by Steinmetz and Barral’s team.