Force and Allostery at the Plasma Membrane: The long and short of it.
| Dates: | 30 June 2014 |
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| Times: | 15:00 - 16:00 |
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| What is it: | Seminar |
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| Organiser: | Faculty of Life Sciences |
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| Speaker: | Robert C. Liddington |
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My laboratory’s first contribution to the cell-matrix field was the structure of the integrin alphaM-I domain in two conformations, on the basis of which we proposed an allosteric model of affinity control and signaling, coined the acronym, “MIDAS”, and noted that the high affinity state was more extended, suggestive of a bond that strengthened upon application of force -- a “catch” bond. The I domain has since emerged as a ubiquitous “catch-bond cassette”, inserted into host cell and matrix proteins, but also hijacked by pathogens (and placed at the tips of their pili), in order to make first contact with the host endothelium under conditions of shear stress, making I domains attractive drug targets for the treatment of inflammation and cancer, as well as novel anti-infectives. On the intracellular side, cell-based work by others has shown that actomyosin-induced force plays an analogous role in controlling cell adhesion, by promoting shape-shifting in key scaffold proteins that modulates their activity. However, we know rather little about the atomic nature of these shape-changes, or how force and ligand-binding collaborate. There has been much work in vitro utilizing peptides/fragments of adhesion molecules, which generally only offer partial insights into mechanism. Therefore, using the example of full-length vinculin, a strongly auto-inhibited but dynamic molecule, I will first describe its equilibrium (ensemble) properties in solution, as well as new structural data on tetrameric vinculin-alpha-catenin and vinculin-talin complexes. I will then compare and contrast these data with the (non-equilibrium) properties of single molecules when stretched at a velocity commensurate with actin-based cell motility. Finally, I will discuss how we want to move these projects forward, with the long-term goal of generating a seamless pathway from our atomic-level work to the impressive cell-based and EM studies performed by members of the Cell-Matrix Centre and others.
Speaker
Robert C. Liddington
Role: Professor
Organisation: Sanford-Burnham Medical Research Institute
Travel and Contact Information
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Lecture Theatre
Michael Smith Building
Manchester
