MechanosensingCells explore their environment by sensing and responding to mechanical forces. Many fundamental cellular processes, such as cell migration, differentiation, and homeostasis, take advantage of this sensing mechanism. At molecular level mechanosensing is mainly driven by mechanically active proteins. These proteins are able to sense and respond to forces by, e.g., undergoing conformational changes, exposing cryptic binding sites, or even by becoming more tightly bound to one another. In humans, defective responses to forces are known to cause a plethora of pathological conditions, including cardiac failure, pulmonary injury and are also linked to cancer. Microorganisms also take advantage of mechano-active proteins and proteins complexes. Employing single-molecule force spectroscopy with an atomic force microscope (AFM) and steered molecular dynamics (SMD) simulations we have investigated force propagation pathways through a mechanically active protein complexes.
Spotlight: Gatekeeper Protein (Oct 2008)
made with VMD
Biological cells are surrounded by a highly versatile, yet very feeble cellular membrane and need to balance differences between the cell's interior and exterior that otherwise would burst the membrane. For example, the osmotic pressures inside and outside the cell need to be closely balanced. Thousands of proteins in the membrane act as gatekeepers, opening pores that can also act as safety valves, helping to reduce the interior-exterior difference in pressure rapidly. One such protein, the mechanosensitive channel of small conductance MscS (see the Mar 2008 highlight, "Observation and Simulation Depict Cell's Safety Valve", the Feb 2007 highlight, "Observing and Modeling a Crucial Membrane Channel", the May 2006 highlight, "Electrical Safety Valve", and the Nov 2004 highlight, "Japanese Lantern Protein") opens in response to cellular membrane tension generated due to a drastic imbalance in osmotic pressure as it arises when a bacterial cell suddenly finds itself in fresh water, rather than a highly saline physiological medium. The MscS channel widens then to jettison molecules out of the cell and reduce tension on the cellular membrane quickly. In a recent report, researchers have combined experimental data from electron paramagnetic measurements and computer modeling to reveal in atomic detail how MscS opens and closes its channel. Combining measurement and modeling, the researchers established a highly resolving computational microscope, unmatched by existing microscopes (more on our MscS website).