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  • The EMBO Journal (2007) 26, 3993 - 4004
  • doi:10.1038/sj.emboj.7601827

Published online: 9 August 2007

Structure of three tandem filamin domains reveals auto-inhibition of ligand bindingEMBO Open

Yatish Lad1,a, Tiila Kiema2,a, Pengju Jiang3, Olli T Pentikäinen4, Charlotte H Coles3, Iain D Campbell3, David A Calderwood1 and Jari Ylänne4

  1. Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT, USA
  2. Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland
  3. Department of Biochemistry, University of Oxford, Oxford, UK
  4. Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland

Correspondence to:

David A Calderwood, Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA. Tel.: +1 203 737 2311; Fax: +1 203 785 7670; E-mail: david.calderwood@yale.edu

Jari Ylänne, Department of Biological and Environmental Science, University of Jyväskylä, 40014 Jyväskylä, Finland. Tel.: +358 14 260 2240; Fax: +358 14 260 2271; E-mail: jylanne@cc.jyu.fi

aThese authors contributed equally to this work

Received 19 April 2007; Accepted 16 July 2007

Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IgFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 Å resolution structure of a three-domain fragment of human filamin A (IgFLNa19–21). The structure reveals an unexpected domain arrangement, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a beta-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20–IgFLNa21 interaction enhances filamin binding to integrin beta-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin–ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure.

  • Keywords:

    • cell adhesion,
    • cytoskeleton,
    • filamin,
    • integrin,
    • X-ray crystallography

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

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