New study on how single cohesin molecules generate force by two distinct mechanisms by Molodtsov lab
4 July 2023
New research by the Molodtsov lab, published in Nature Communications, on how single cohesin molecules generate force by two distinct mechanisms.
Cohesin is a protein complex that was identified for its function in physically holding two sister DNAs during cell division, which is essential for correctly passing genomes from one generation to another. Recent research just in the last few years, discovered that cohesin has another role – it can spatially organize DNA, which is important for gene expression, repair and recombination. Cohesin can move along DNA and extrude DNA loops. However, how a single molecule of cohesin can work as a molecular machine performing these mechanical functions is poorly understood.
Cohesin can undergo two major conformational changes: the bending of the molecule’s long coiled-coil domains and the engagement/disengagement between the cohesin’s two ATPase head domains. In order to propel itself along the DNA and generate DNA loops, conformational changes in cohesin must generate mechanical force and determining these forces is essential for understanding the mechanism of cohesin movement. To achieve this, we used optical tweezers, which was previously instrumental for understanding how other molecular machines such as kinesin, dynein or myosin, generate forces.
We discovered that the two conformational changes in cohesin generate forces by different molecular mechanisms. The bending of coiled coils is driven by the Brownian fluctuations, happens even in the presence of non-hydrolysable ATP analogues and generates only weak force. On contrary, the ATPase head engagement is a power stroke that uses energy of ATP to generate strong forces. We showed that the high energy of the ATPase engagement may be stored in the mechanically strained form of the part of the cohesin complex and released during the disengagement, essentially working as a small molecular spring. These findings suggest that cohesin combines two unconventional force generating activities in one molecule and pay the way for understanding how these activities may power different aspects of cohesin-DNA interaction.
Links
- Research article in Nature Communications
- Professor Maxim Molodtsov's academic profile
- UCL Physics & Astronomy
- UCL Institute for the Physics of Living Systems