Two New Papers on Integrin Activation

Just as I was in the process of finishing my doctorate in August, I found out that my first first-author paper had been accepted for publication by The EMBO Journal. This was good news, because we were reporting some pretty fundamental findings in a relatively saturated field, and one of our competitors had managed to successfully stall the acceptance of this paper since March. Up until that point, witnessing this happen firsthand had been a somewhat frustrating and disillusioning experience for a young scientist, but I think that we were vindicated in the end. Anyway, this paper--and another paper that I contributed to--were published online earlier this month.

These studies both explore the important biological process of integrin activation. The first paper (Anthis et al.) provides some new basic molecular details for how this process is carried out in the cell. Cells in humans and other higher organisms exist in a dynamic environment, alternately grasping and disengaging from the three-dimensional web of their surroundings (i.e. the extracellular matrix). Many of these tasks involve a family of proteins called integrins, which act as the "hands" of the cell. The cell internally controls whether an integrin is adhesive by signals from within the cell, using another protein called talin. By exploring the detailed three-dimensional structure of a talin/integrin complex, we showed how key interactions between talin, the integrin, and the inner surface of the cell membrane can elegantly promote the structural changes outside the cell that modulate adhesion strength.

The following figure (from my thesis) illustrates the process of integrin activation:

On the left is the inactive integrin (bent over, not bound to the extracellular matrix), and on the right is the active integrin (extended, bound to the matrix). All of the major structural changes happen outside of the cell (where the integrin binds to the matrix), but these changes are controlled from inside of the cell, by the binding of talin to the integrin. Quite a bit was already known about this process, but we were able to give the first truly comprehensive mechanism for how this process happens in the cell.

The following animation illustrates our new model. It is shown in a slightly different orientation from the figure above (supplementary movies in two other orientations were published online with the paper, including in the same orientation as the above figure), but basically this is just the bottom half of the figure above-- but only showing the parts of the integrin inside the cell and the parts embedded in the membrane.

The two parts of the integrin are shown in red and blue, and talin in yellow. In the inactive state, the two parts of the integrin are bound to one another (and this is what keeps the integrin in the inactive state). Talin breaks this interaction, causing the parts of the integrin in the cell and in the membrane to separate, leading to the extended active state outside of the cell. In the new model of integrin activation we present in our paper, talin breaks this interaction by directly interfering with it and by causing one of the parts to rotate away from the other. In this animation, the red and blue spheres are contacts between the two integrin parts, and you can see that these contacts disappear as integrin activation proceeds.

Although much of this work was completed in Iain Campbell's lab at the University of Oxford, this paper was definitely a team effort (involving two other labs: Mark Ginsberg's at UCSD and David Critchley's at the University of Leicester), and all eleven authors contributed substantially. We were only able to craft our new model by undertaking an interdisciplinary approach--using structural, biophysical, and cellular biological techniques. Although proteins are very large as far as molecules are concerned, they are much too small to be seen directly (at least in any great detail) by a light microscope. So, in order to determine the 3D structures of proteins, we have to use one of two indirect techniques: NMR or X-ray crystallography. Although I'm primarily an NMR scientist, I used X-ray crystallography (with much assistance from others) to solve the structure of the talin/integrin complex that we present in our paper. Still, NMR played a very important role in other aspects of this paper.

The protein structure presented in the second paper (Goult et al.), however, was solved by NMR. This work was spearheaded by Ben Goult in David Critchley's lab, and I admittedly only made a minor contribution to it. Ben's paper explores a different aspect of integrin activation: the role of another protein, kindlin. For a long time, it has been known that talin is the primary direct activator of integrins. However, it has recently emerged that kindlin also plays a role in integrin activation. The exact role of kindin in integrin activation remains unclear, but Ben's paper offers new insight into this process.

One of the exciting aspects of these papers is that neither is the final word on the subject, and there is still quite a bit of work to be done on both stories. Also, we still have a few more integrin activation papers on the way, so stay tuned for more!

Anthis NJ, Wegener KL, Ye F, Kim C, Goult BT, Lowe ED, Vakonakis I, Bate N, Critchley DR, Ginsberg MH, & Campbell ID (2009). The structure of an integrin/talin complex reveals the basis of inside-out signal transduction. The EMBO journal PMID: 19798053

Goult BT, Bouaouina M, Harburger DS, Bate N, Patel B, Anthis NJ, Campbell ID, Calderwood DA, Barsukov IL, Roberts GC, & Critchley DR (2009). The Structure of the N-Terminus of Kindlin-1: A Domain Important for alphaIIbbeta3 Integrin Activation. Journal of molecular biology PMID: 19804783