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Keeping the steps of cell division in line: Research investigates protein cyclin B's role

A "pocket" on the protein cyclin B is responsible for ensuring that the steps of cell division take place in the correct order. Two studies by researchers at the University of Konstanz investigated why this is the case. The studies have been published in and .

Cell division is key for life. Every organism—from the smallest yeast to complex human beings—depends upon the constant reproduction of individual cells. In this process, various mechanisms ensure that all of the steps are completed in the correct order and that no errors are incorporated into new cells. This is important because such errors can, for example, cause tumors to form.

A research team at the University of Konstanz led by biologist Thomas Mayer has now discovered that one of these control mechanisms is guided by a small binding-pocket that helps cyclins from the B type to dock onto substrates and thus significantly impacts the correct sequence of cell division events.

The correct sequence of events is key

During cell division, it is important that the many individual steps always occur in exactly the same order. If this does not happen, it results in malformations. Depending on the cell involved and the step in the process, this can, for example, lead to the formation of tumors or to infertility.

"In two studies, we tested whether the docking site on cyclin B—a type of pocket—contributes to the correct sequence of events and, if so, what effects it has," Mayer says.

"By making targeted changes to this docking site, we were able to demonstrate that malformations occur during cell division when the pocket loses its shape and can no longer dock onto the substrate."

The reason for this lies in the cyclins' cooperation with a kinase. Kinases are responsible for phosphorylating amino acids in substrates—a key process for cell division. Another important factor for the process is that the environment of the amino acids has a significant influence on how well phosphorylation takes place.

If the kinase floats freely in the cell, it mainly phosphorylates amino acids that are in an ideal environment.

"However, if cyclin B docks onto substrates via its pocket, then the kinase 'piggybacks' into the spatial proximity of these substrates. This enables the kinase to also phosphorylate amino acids that are in a less ideal environment," Thomas Mayer explains.

"Basically, the pocket of cyclin B functions like a Velcro fastener connecting the kinase and the substrate. This, in turn, contributes to the correct sequence of events in cell division."

No pocket = no correct cell division

The research team led by Thomas Mayer has now demonstrated this mechanism for two cyclins from the B group. Cyclin B1 is relevant in mitosis, a type of cell division. The researchers observed how cyclin B1 docks onto substrates with its pocket and influences the behavior of the kinase as a result.

"As a cross-check, we looked at what happens if the pocket on cyclin B1 is either missing or no longer fits. For this, we mutated the pocket and were able to observe that mitosis no longer proceeds correctly," Mayer explains. This can, for example, cause errors in the separation of chromosomes that result in mitosis proceeding either more slowly or incorrectly, which, in turn, can lead to the formation of tumors.

Cyclin B3, on the other hand, plays an important role in meiosis, another type of cell division. It is responsible for ensuring that meiotic division takes place correctly and that a healthy egg cell can develop. In the study, the process was intentionally disrupted by a change in the cyclin B3 pocket, which resulted in the egg cell not maturing.

"A faulty pocket on cyclin B3 can therefore be one cause of infertility," Mayer concludes.

"Researchers already knew that such pockets exist on the cyclins of the B group. However, we have now been able to document, for the first time, how relevant it is for the correct sequence of events in cell division," Mayer says.

This work lays the foundation for further research contributing to an ever better understanding of cellular processes and, as a result, to the more targeted treatment of illnesses.