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

Journal article

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 A 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.

Authors: Lad, Y; Kiema, T; Jiang, P; Pentikäinen, O; Coles, C

• Publication status: Published
• Journal: EMBO journal
• Volume: 26
• Issue: 17
• Pages: 3993-4004
• Publication date: 2007-09-01
• DOI: 10.1038/sj.emboj.7601827
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: Microfilament Proteins; Humans; Filamins; Models, Molecular; Protein Structure, Tertiary; Integrins; Contractile Proteins; Protein Binding; Ligands