Mechanosensing
Cells 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: Unraveling Outer Membrane Transport (Jul 2007)
Like all organisms, bacteria have to eat. However, bringing nutrients in from the outside world is not an easy task for many bacteria that are surrounded by an extra membrane. The second membrane, called the outer membrane, offers additional protection but at a cost: no energy can be generated or stored at the outer fringes of the cell. So, to import large, rare nutrients that cannot cross by diffusion alone, bacteria have evolved a unique transport system which couples the inner, energy-generating membrane to the passive outer membrane, known as the TonB-dependent transport system. TonB, an inner membrane-associated protein, transfers energy across the periplasm to a variety of outer-membrane transporters. These transporters have a large, beta-barrel structure which is blocked in the middle by a plug called the 'luminal domain'. How TonB transfers energy to the transporter and causes the luminal domain to come out is still a mystery though. Now with the help of computer simulations using NAMD and a recent crystal structure of TonB coupled to BtuB, the transporter responsible for vitamin B12 transport, researchers have shown that TonB can mechanically activate the transporter by pulling on the luminal domain, causing it to leave the barrel. Using steered molecular dynamics, it was found that TonB stayed firmly attached to the luminal domain of BtuB, even though the contact between the two is limited to just a handful of residues. Furthermore, this pulling initiated unfolding of the luminal domain, opening a transport pathway for the substrate. These results, the subject of a recent publication and also highlighted in Science, demonstrate how a mechanical coupling can bridge the gap between the two membranes, thus enabling outer membrane transport.
