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

: Lad Y, Kiema T, Jiang PJ, Pentikainen OT, Coles CH, Campbell ID, Calderwood DA, Ylaenne J

Publisher: NATURE PUBLISHING GROUP

: 2007

: EMBO Journal

: EMBO JOURNAL

: EMBO J

: 26

: 17

: 3993

: 4004

: 12

: 0261-4189

DOI: https://doi.org/10.1038/sj.emboj.7601827

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 2.5A 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.