Journal
EMBO JOURNAL
Volume 26, Issue 17, Pages 3993-4004Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601827
Keywords
cell adhesion; cytoskeleton; filamin; integrin; X-ray crystallography
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Funding
- NIGMS NIH HHS [R01 GM068600-05, R01 GM068600, R01 GM068600-04, R01 GM068600-01, R01 GM068600-06] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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.
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