posters 5th Asia-Pacific NMR Symposium 2013

Unravelling the Mechanism of Integrin Activation Using NMR (#223)

Kate L Wegener 1 2 , Anthony W Partridge 3 , Antreas C Kalli 1 , Mark SP Sansom 1 , Mark H Ginsberg 3 , Iain D Campbell 1
  1. Department of Biochemistry, University of Oxford, Oxford, UK
  2. Adelaide University, Adelaide, SA, Australia
  3. Department of Medicine, University of California San Diego, La Jolla, California, USA

Integrins are essential cell surface receptors with key roles in cell migration and adhesion. They are heterodimeric proteins made up of an alpha and a beta subunit, with each subunit comprised of a large extracellular domain, a single pass transmembrane helix and a short, largely unstructured cytoplasmic ‘tail’. Using NMR, we showed that the integrin activating protein talin binds to the membrane proximal region of the beta-integrin tail. The structure of this complex was solved using a chimeric integrin/PIP-kinase peptide, designed to boost the interaction affinity. Further investigations confirmed that the structure observed is also found with the native integrin peptide. Additional studies using NMR and liposomes, identified a cationic patch on the talin surface that interacts with the anionic lipid bilayer.

Binding of talin to both the membrane and the beta-integrin cytoplasmic tail, causes the beta-integrin transmembrane helix to separate from the alpha-subunit, leading to conformational rearrangement of the integrin extracellular domains, and subsequent ligand binding.