Using a permeabilized cell system and cell physiology to understand cytokinetic actomyosin ring constriction (part of programme Cytokinetic actomyosin ring: from understanding the ultrastructure and assembly to elucidating forc... ).
Every time a cell divides, a ring of protein fibres must cinch tight like a purse string to split the cell in two—but after 40 years of study, no one knows exactly how that ring generates force. This project tackles that fundamental gap. The ring is made of actin filaments and myosin motors, the same proteins that power muscle contraction, yet how they work together to constrict during cell division remains a mystery. The researchers have built a system where they can trigger ring contraction in a test tube by adding energy molecules, letting them watch the process directly. They will measure the force the ring produces, identify which proteins are essential for constriction, and track how the ring’s molecular structure changes as it tightens. This is fundamental science with no immediate practical application. But understanding how actin and myosin generate force in a dividing cell could eventually inform treatments for diseases where cell division goes wrong—such as cancer—or inspire synthetic systems that mimic biological contraction. Past work on the same protein machinery led to insights into muscle disease and drug development; this project could open similar unexpected doors.
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Cell division in many eukaryotes requires an actomyosin-based contractile ring, whose constriction bisects a mother cell into two. Although this F-actin and myosin II motor-containing ring has been described for >40 years, we know very little about how it constricts and generates force. Our goals are to understand the mechanism of actomyosin ring constriction and its regulation in the cell cycle. We will use Schizosaccharomyces pombe for our studies, since it divides using an actomyosin-based co ntractile ring, and is amenable to the methods of genetics, biochemistry, and cytology. We have developed a permeabilized cell system in which addition of adenosine triphosphate leads to complete contraction of intact actomyosin rings. We will use this system to 1. estimate the force generated by the constricting ring and 2. perform contractility assays on permeabilized cells generated from mutants in actomyosin ring proteins, to identify ring components important for its constriction. We wil l use proteomic approaches to uncover the molecular differences between actomyosin rings before and during constriction and to understand the cell cycle regulation of ring constriction. We will use cross-linking amino acid mutagenesis of actin to identify changes in actin filaments during cytokinesis and employ a new approach to identify protein conformational changes during cytokinesis. Finally, we will investigate if overlapping mechanisms regulate ring constriction in vivo. The combination of in vitro contractility, in vivo studies, and screens based on emerging technologies should provide tremendous insight into actomyosin ring constriction mechanisms and can lead the field in new directions.
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