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

✍ Scribed by Lad, Yatish; Kiema, Tiila; Jiang, Pengju; Pentikäinen, Olli T; Coles, Charlotte H; Campbell, Iain D; Calderwood, David A; Ylänne, Jari

• Book ID: 110032200
• Publisher: Nature Publishing Group
• Year: 2007
• Tongue: English
• Weight: 446 KB
• Volume: 26
• Category: Article
• ISSN: 0261-4189
• DOI: 10.1038/sj.emboj.7601827

✦ Synopsis

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.