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September 16, 2016

Bacterial second messenger switches enzyme into “reverse gear”

The signaling molecule c-di-GMP plays a crucial role in bacterial reproduction. It controls cell division by shifting gears of a key cell cycle enzyme from forward to backward. The molecular mechanism of this switch has been unraveled by the team of Prof. Tilman Schirmer at the Biozentrum, University of Basel. The results have now been published in the journal “Science Advances”.

The second messenger c-di-GMP (centre) stabilises the open structure of the histidine kinase to allow removal of the phosphate on a target protein.

All cells including bacteria in order to propagate need to continuously progress through the cell cycle, a strictly controlled succession of cell growth and division. In bacteria, cell cycle progression is controlled by histidine kinases. Last year, researchers at the Biozentrum of the University of Basel showed that the second messenger c-di-GMP tightly regulates the activity of such a kinase in the bacterium Caulobacter crescentus. In this follow-up study, the teams led by Prof. Tilman Schirmer and Prof. Urs Jenal have now elucidated how c-di-GMP rearranges the enzyme structure to trigger the switch between its two antagonistic activities.

Signaling molecule switches enzyme into “reverse gear”

During the cell cycle cells continuously alternate between periods of DNA synthesis and cell division, with each passage generating two new daughters from one parent cell. This is a highly coordinated process enabling the faithful transfer of genetic information to the next generations. How these highly precise processes are regulated in the cell is subject of intense studies. Recent studies indicated that in bacteria, c-di-GMP oscillations determine when cells need to initiate the duplication of their chromosomes. In this process, this signaling molecule forces a histidine kinase to switch from forward into reverse gear and thus ultimately controls the progression of the cell cycle.

Generally, histidine kinases are in “forward gear” mode with the enzyme transferring phosphate groups to downstream proteins. In Caulobacter this results in blocking chromosome replication and, as a consequence, cell division. “In its default mode, the enzyme is found in a closed structure. However, in presence of c-di-GMP, an open structure is stabilized by cross-linking of two binding sites on the enzyme surface,” explains Badri Dubey, the first author of the study. “In its open form, the histidine kinase works ‘in reverse’ and removes the phosphate groups from its target proteins, thus lifting the replication and cell division block. With our crystallographic and biochemical analyses, we have now, for the first time, deciphered the molecular mechanism of how c-di-GMP can regulate the two diametrically opposed reactions of a bifunctional enzyme,” says Schirmer.

A three billion year old control mechanism

Using bioinformatics the researchers were able to show that the identified c-di-GMP binding sites are conserved in a large group of bacterial histidine kinases. Because such presumably c-di-GMP regulated enzymes were identified in various distantly related branches of the bacterial taxonomic tree, the authors speculate that the regulatory mechanism they discovered evolved early in evolution and has been acquired more than three billion years ago.

Original article:
Badri N. Dubey, Christian Lori, Shogo Ozaki, Geoffrey Fucile, Ivan Plaza-Menacho, Urs Jenal, Tilman Schirmer. Cyclic di-GMP mediates a histidine kinase/phosphatase switch by noncovalent domain cross-linking. Science Advances, published online 16 September 2016.

Contact: Communications, Katrin Bühler