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Igor L. Barsukov

Igor L. Barsukov

University of Liverpool, UK

Title: LD Motif Interacting networks in cell-matrix adhesion.

Biography

Biography: Igor L. Barsukov

Abstract

Statement of the Problem: Cell-matrix adhesion requires assembly of large multi-protein complexes linked to the cyto-domains on the integrin adhesion receptors. These complexes dynamically change in response to the adhesion forces and environmental signals. Mechano-sensitive adaptor protein talin couples the force and adhesion signaling by acting as a hub for numerous, often competitive, interactions. The molecular mechanism that controls the co-ordination of the interactions in time and space is currently not understood. The aim of this study is to define the interactions between talin and Rho-GAP Deleted in Liver Cancer 1 (DLC1) that regulates adhesion forces. Methodology: Structure of the talin/DLC1 complex was solved by X-ray crystallography and the interactions between the proteins analysed by NMR spectroscopy. Fluorescent imaging was used to define the interactions within the adhesion complexes and cancer cell lines were employed to characterise the effect of the interaction on the biological activity. Findings: We defined the atomic details of the talin/DLC1 interactions and used this information to identify signalling protein paxillin as a talin ligand. Based on the structural information we designed a range of talin mutants that modulate the interactions and demonstrated that the mutations reduce DLC1 signalling in adhesion. Conclusion & Significance: Talin recognises LD motifs in DLC1 and paxillin through a set of well-defined charge interactions. These interactions are similar to other LD motif interactions previously identified in signalling pathways. These interactions are also similar to the interactions between talin, RIAM and vinculin that were previously not assigned to the LD motif family. Together, the relatively weak LD motif interactions within the adhesion complex create a protein network that could dynamically respond to the adhesion signals.

References:

  1. Zacharchenko, T., et al., LD Motif Recognition by Talin: Structure of the Talin-DLC1 Complex. Structure, 2016.
  2.  Atherton, P., et al., Vinculin controls talin engagement with the actomyosin machinery. Nat Commun, 2015. 6: p. 10038.
  3.  Goult, B.T., et al., RIAM and Vinculin Binding to Talin Are Mutually Exclusive and Regulate Adhesion Assembly and Turnover. J Biol Chem, 2013. 288(12): p. 8238-8249.
  4.  Goult, B.T., et al., Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: Implications for talin activation. J Struct Biol, 2013. 184(1): p. 21-32.
  5. Elliott, P.R., et al., The Structure of the Talin Head Reveals a Novel Extended Conformation of the FERM Domain. Structure, 2010. 18(10): p. 1289-1299.