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: Biological Flow Sensor (Sep 2010)
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The human body is protected by self-healing mechanisms, one of them being instant blood clotting at a bleeding site after blood vessel injury. What triggers the formation of a blood clot? Researchers found that a protein on blood platelets, called GPIbα, functions as a sensor of so-called high shear flow caused by bleeding. A loop-shaped, 17-amino-acid-long, segment of GPIb&alpha, the β-switch, acts as the flow sensor. Once a blood vessel is injured, bleeding increases shear stress due to blood flow at the wound, which in turn induces the β-switch to change from a loose, loop-shape to an elongated, hairpin-shape, the latter referred to by researchers as a β-hairpin. This conformational change makes GPIbα stick better to the damaged vessel and eventually leads to blood clotting, which heals the vessel. In a prior study (see the Jul 2008 highlight, Molecular Flow Sensor Triggers Wound Healing), Molecular dynamics simulations using NAMD and VMD provided already a microscopic view of the flow-induced loop to β-hairpin transition. A recent study extended the investigation of the remarkable biological flow sensor, detailing the flow rate needed to trigger it and identifying the detailed sensor mechanism. A combination of simulation and mathematical analysis revealed the β-switch as a system of two stable states, one disordered, with loop geometry and one ordered, with β-hairpin geometry. Normal flow prefers the disordered state; high shear flow prefers the ordered state, inducing thereby the life saving transition. More on our flow sensor website.
