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DOME Sintesi della relazione

Project ID: 261105
Finanziato nell'ambito di: FP7-IDEAS-ERC
Paese: France

Final Report Summary - DOME (Dissecting a Novel Mechanism of Cell Motility)

The ambition of this ERC grant was to elucidate the long mysterious mechanism by which bacteria move across solid surfaces. This question is of large biological significance because surface motility is important for the formation of antibiotic resistant biofilms in many bacteria, including pathogens. We initially proposed to study Myxococcus xanthus, a soil-dwelling organism with a fascinating multicellular lifestyle. In this bacterium, surface motility drives the cooperation of thousands of cell that form differentiated fruiting body structures when the nutrients run low in the environment. Although the biology of Myxococcus has been studied for half a century, the mechanism by which it moves on surfaces has remained an enigma preventing any deep study of how this process contributes to the lifecycle. At the beginning of the ERC grant, we had discovered genes that encode possible components of the motility complex for the first time, we had also shown that some of these components localized at fixed sites along the bacterium’s cell axis, analogous to focal adhesion complexes in eukaryotic cells; however, how these proteins propel the Myxococcus cell was not elucidated. DOME proposed to use a large-scale interdisciplinary approach to investigate i) the molecular mechanism of motility and ii) how cells make directional decisions to synchronize their movements.
In the course of the ERC grant period, we have elucidated the motility mechanism for the first time. The motility complex (named Agl-Glt) is a multi-tiered protein complex that assembles in the bacterial envelope. The assembly occurs at the leading cell pole of the bacterium by direct recruitment to the bacterial actin cytoskeleton (MreB) via the small Ras-like protein MglA. The complex then moves directionally toward the lagging cell pole, propelling the cell as it attaches the underlying surface via outer membrane adhesion factors. We have precisely identified the motor complex and shown that it moves along a helical track in the cell envelope. Thus, the cell rotates along its longitudinal axis as it moves forward. At the lagging cell pole, the motility complex is disassembled, simply by disrupting the interaction between MglA and actin. MglA and its regulator MglB act at the corner of assembly and regulation because their localization can be switched synchronously to the opposite cell pole (reversal), provoking movement in the opposite direction. We identified critical factors underlying this regulation. Specifically, the localization of MglA is regulated by a receptor/kinase chemosensory-type complex (Frz). In this process the kinase phosphorylates two spatial regulators that act sequentially to target of MglA to the pole and detach it when reversal signals are emitted by the kinase. Thus, the cell polarity of Myxococcus cells can be switched by signal transduction acting like a molecular compass in response to environmental signals.
The discovery of the Myxococcus motility complex and its regulation shed light on the evolutionary origin of motility in bacteria and revealed that it emerged by a three-step process where an ancestral bacterial signaling pathway (Frz) first recruited a eukaryotic-type G-protein module (MglAB), which subsequently recruited the motility complex (Agl-Glt). The motility complex itself evolved recently from an ancient molecular complex that is widespread in bacteria. However, these complexes are likely not motility complexes because they lack proteins, which we find are critical for motility. In fact, we studied the function of one of these complexes as one of them (Agl-Nfs) is also encoded by the Myxococcus genome in addition to the motility apparatus. We found that Agl-Nfs assembles specifically in Myxococcus spores and promotes assembly of the polysaccharidic spore coat. Similar to the motility complex the Agl-Nfs complex moves along the spore cell envelope, but in this case because the outer parts of the complex are directly linked to the main spore coat polymer, this movement winds the spore coat around the spore envelope. Thus, the Myxococcus motility complex could have emerged from a new class of bacterial cell envelope assembly system. Investigating the function of related complex will be an important post-ERC direction because it may explain fundamentally how large macromolecular complexes evolve for specific tasks, a major question in biology.

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