Cells in higher organisms exist in a dynamic environment, requiring the ability to alternately grasp and disengage from the three-dimensional web of their surroundings. One family of proteins in particular, the integrins, plays a key role in this process by acting as the hands of the cell. Spanning the cell membrane, they link the extracellular matrix to the cell's internal cytoskeleton. Integrins are especially interesting, though, because the cell uses them to uniquely pass signals in both directions across the membrane, and an integrin's adhesiveness for the extracellular matrix can be activated from within the cell by a protein called talin. This occurs through a direct protein-protein interaction between talin and the integrin.
Some biological processes call for exquisitely fine regulation of cell adhesiveness. When a cell migrates from one location to another in the body (as is necessary in growth, development, wound healing, and blood vessel formation, for example) integrins at the front of the cell need to make new contacts with the surroundings, but those in the rear need to disengage. Specifically, this requires the regulation of integrin activation by talin.
We have a new paper out this week in JBC (The Journal of Biological Chemistry) that explains part of this regulation in great structural detail. This work was done primarily by Ben Goult, a postdoc with David Critchley at the University of Leicester.
Talin is a very long protein consisting of many individual domains. Although the structures of these domains (individually or in groups) are virtually all known, what the entire protein looks like when all of these domains are together remains somewhat undefined. It has long been suspected that talin autoinhibits itself, though. Only one of the many domains in talin actually binds to and activates integrins, and this activity is greatly reduced in the intact talin protein.
The new paper shows that this talin autoinhibition is the result of another talin domain binding to the integrin-activating domain. Ben used NMR to solve the atomic-resolution structure of this competing domain alone and in complex with the integrin-activating domain. The structure revealed that this intermolecular interaction between these two domains physically blocks the integrin binding site, thus explaining talin autoinhibition. I validated this by performing my own NMR-based experiments demonstrating that the presence of this other domain inhibits the talin/integrin interaction.
By producing talin in a default inactive state, this gives the cell the ability to fine-tune integrin activation, as the cell has a variety of mechanisms at its disposal to rapidly and reversibly release autoinhibition. We previously explored another tool that the cell uses to control integrin activation: phosphorylation of the integrin, which directly disrupts the talin/integrin interaction. Together, these processes allow the cell to elegantly regulate its adhesiveness and respond to constantly changing conditions within the body.
Goult, B., Bate, N., Anthis, N., Wegener, K., Gingras, A., Patel, B., Barsukov, I., Campbell, I., Roberts, G., & Critchley, D. (2009). The structure of an interdomain complex which regulates talin activity Journal of Biological Chemistry. (link)
Very interesting work, dude!