Structure of three tandem filamin domains reveals auto-inhibition of ligand binding

• Yatish Lad ^[1] ; Tiila Kiema ^[2] ; Pengju Jiang ^[3] ; Olli T Pentikäinen ^[4] ; Charlotte H Coles ^[3] ; Iain D Campbell ^[3] ; David A Calderwood ^[1] ; Jari Ylänne ^[4]
  1. [1] Yale University

     Yale University

     Town of New Haven, Estados Unidos

     
  2. [2] University of Oulu

     University of Oulu

     Oulu, Finlandia

     
  3. [3] University of Oxford

     University of Oxford

     Oxford District, Reino Unido

     
  4. [4] University of Jyväskylä

     University of Jyväskylä

     Jyväskylä, Finlandia

     

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 26, Nº. 17, 2007, págs. 3993-4004
• Idioma: inglés
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• Resumen

  • 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 β-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 β-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.