Featured Article - July 2014
Short description: In the absence of a 3D crystal structure of talin, a structural model based on EM reconstruction and known structures of individual domains provides insight into its mechanism of action.
Talin is one of several proteins that activate integrins—transmembrane proteins involved in cell adhesion—and link them to the actin cytoskeleton. This adaptor protein comprises an N-terminal head domain, followed by a flexible rod made up of 62 α-helices organized into 13 domains, and a C-terminal dimerization helix.
Critchley, Volkmann, Hanein and colleagues (PSI CELLMAT) have solved structures of individual and combinations of talin domains by NMR spectroscopy or X-ray crystallography. By adding small-angle X-ray scattering data, they determined relative orientations of all domains within the full protein. This analysis revealed that the domains are connected by hinge-like linkers, which enable talin to flexibly connect to actin at various distances.
Purified full-size talin, however, exists as a compact, globular homodimer. Electron microscopy (EM) followed by single-particle reconstruction resulted in a three-dimensional (3D) reconstruction with ∼2.5-nm resolution after optimization. The rods were arranged in a donut shape, with the head domains occupying the center and thus burying the protein's integrin-binding site, rendering it inactive. NMR-based fragment-competition analysis confirmed known interactions and revealed new weak interactions in the auto-inhibited state of talin that were consistent with the EM model.
This modeling, combined with information from prior work, provides clues about how talin functions: the authors conclude that auto-inhibited talin must unravel in order to expose integrin-binding sites and connect with actin.
B.T. Goult et al. Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation.
J. Struct. Biol. 184, 21-32 (2013). doi:10.1016/j.jsb.2013.05.014