Today nanotechnology enables us to attract individual molecules mechanically, allowing their behaviour when exposed to a mechanical force to be observed. With the aid of computer simulations, ETH Zurich researchers can now illustrate how a particular scaffolding protein in the bonding between the extra-cellular matrix and the internal cytoskeleton can be activated by exerting force upon it.
For a cell to survive, most eukaryotes have to be anchored to their surroundings mechanically. This is achieved by special proteins, the integrins, which cross the cell membrane. They are connected to the external periphery of the cell, the so-called extra-cellular matrix, and the cell interior, the cytoskeleton, by scaffolding proteins such as talin. Vesa Hytönen, a post-doc at the Laboratory for Biologically Oriented Materials at ETH Zurich, and Viola Vogel, Professor of Biologically Oriented Materials, also at ETH Zurich, have succeeded in revealing a mechanism as to how the scaffolding protein can recruit the protein vinculin when exposed to a force and bind with it. In a state of equilibrium, talin would not do this without force.
Water activates restructuring
The researchers can now demonstrate on an atomic scale how the structure of the scaffolding protein talin changes if force is exerted upon it using high-resolution computer simulations. Talin consists of several tightly packed helix bundles. If it is stretched mechanically, the bundles break into several smaller bundles that remain interconnected. Consequently, in the case of talin, vinculin binding sites located on hidden helixes are laid open. This happens when water molecules infiltrate the talin and moisten the hydrophobic sections of individual talin helixes.
As these helixes have an aversion to water, they try to hide their hydrophobic sections by forming complexes with other proteins – in this case, vinculin. Water thus activates the structural exchange of an entire talin helix, which is still bound like a washing line at the ends with talin but which structurally forms a complex with vinculin. According to Viola Vogel, vinculin’s complementary helix bundle structure makes this possible. Like talin, vinculin can then also connect to the cytoskeleton and thus mechanically reinforce the scaffolding between the interior and exterior.
“Previously, research primarily concentrated on the relationship between the structure and function of proteins that are in equilibrium with their surroundings”, explains Viola Vogel. For the last few decades, as nanotechnology established itself and began to be researched in billionths of a meter, it has been possible to investigate the mechanical properties of proteins and pursue the question as to how mechanical forces govern the way the proteins work.
New field of research
Vogel states that the new computerized results explain all previous laboratory experiments. Today, we only know how very few proteins are altered biochemically or even activated and deactivated by mechanical forces. The fact that proteins can be activated by mechanical forces by exchanging a helix, however, is still something special. According to Vogel, there is still a lot of work to be done in this new field of research. In future, these results might be used in biotechnology or medicine.
Journal eference: Hytönen, V. & Vogel, V.: How Force Might Activate Talin’s Vinculin Binding Sites: SMD Reveals a Structural Mechanism, PLoS Computational Biology 4 (2008), doi:10.1371/journal.pcbi.0040024
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