Editors' ChoiceMechanotransduction

Tailoring talin function

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Science Signaling  14 Apr 2015:
Vol. 8, Issue 372, pp. ec90
DOI: 10.1126/scisignal.aab3213

Talin is a multidomain adaptor protein that links integrins to the cytoskeleton. An integrin-binding site in the N-terminal head domain (IBS1) of talin is important for mediating activation of integrins to enhance adhesion to the extracellular matrix, a process called inside-out signaling. When integrins bind the extracellular matrix proteins, force is exerted on talin, a process called outside-in signaling, through a second integrin-binding site in the C-terminal rod domain (IBS2). Outside-in signaling changes the conformation of talin to expose a binding site for vinculin, which links talin to the actin cytoskeleton. Binding sites in both the N and C termini of talin also interact directly with actin. Klapholz et al. found that different cell adhesion contexts in Drosophila melanogaster required different configurations of the integrin-talin-vinculin complex. To mediate embryonic muscle attachment to the extracellular matrix, talin required IBS1 and either the vinculin-binding site (VBS) or the C-terminal actin-binding domain (ABD). However, only when all three domains (IBS1, VBS1, and ABD) were present were all muscles fully attached. IBS2 was dispensible for talin to mediate embryonic muscle attachment. In constrast, embryonic epidermal morphogenesis required IBS2, VBS, and ABD, but the IBS1 portion of the head domain was not required in this context. Proper adhesion of epithelia in the developing wing required all four domains. In this context, mutant talins containing one IBS and either VBS or ABD retained partial function. Fluorescence energy transfer (FRET) and superresolution microscopy suggested different configurations of the integrin-talin-vinculin complex in each context. In wing epithelia, talin is likely stretched out along the plasma membrane in a tail-to-tail orientation, with IBS1, IBS2, ABD, and VBS all engaged. In the embryonic epidermis, talin is also stretched out along the membrane in a tail-to-tail orientation, but with only IBS2 engaged in integrin binding. In this context, ABD is bound to cytoplasmic actin, and the VBD mediates interaction with membrane-associated actin or some other membrane component. At muscle attachment sites, only the head domain of talin associates with integrin at the membrane through IBS1. The rest of the protein extends into the cytoplasm, with both VBS and ABD mediating interactions with cytoplasmic actin. The authors propose that force exerted on talin through the ABD or VBS is required to pull IBS2 away from the membrane for muscle attachment. These findings imply that different configurations of the integrin-talin-vinculin complex may enable talin to sense the different forces experienced by each tissue.

B. Klapholz, S. L. Herbert, J. Wellmann, R. Johnson, M. Parsons, N. H. Brown, Alternative mechanisms for talin to mediate integrin function. Curr Biol. 25, 847–857 (2015). [PubMed]

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