Structure of three tandem filamin domains reveals auto-inhibition of ligand binding.
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.
Lad
Yatish
Y
Department of Pharmacology and Interdepartmental Program in Vascular Biology and Transplantation, Yale University School of Medicine, New Haven, CT 06520, USA.
Kiema
Tiila
T
Jiang
Pengju
P
Pentikäinen
Olli T
OT
Coles
Charlotte H
CH
Campbell
Iain D
ID
Calderwood
David A
DA
Ylänne
Jari
J
D003285:Contractile Proteins / Q000737:chemistry* / Q000378:metabolism; D064448:Filamins; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D008024:Ligands; D008840:Microfilament Proteins / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D003285:Contractile Proteins; D064448:Filamins; D016023:Integrins; D008024:Ligands; D008840:Microfilament Proteins
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