The Molecular Basis of Filamin Binding to Integrins and Competition with Talin

• Published in: Molecular cell 2006-02, Vol.21 (3), p.337-347
• Main Authors: Kiema, Tiila, Lad, Yatish, Jiang, Pengju, Oxley, Camilla L., Baldassarre, Massimiliano, Wegener, Kate L., Campbell, Iain D., Ylänne, Jari, Calderwood, David A.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Binding Sites; Calpain - metabolism; CELLBIO; Contractile Proteins - chemistry; Contractile Proteins - genetics; Contractile Proteins - metabolism; Crystallography, X-Ray; Filamins; Integrin beta Chains - chemistry; Integrin beta Chains - metabolism; Mice; Microfilament Proteins - chemistry; Microfilament Proteins - genetics; Microfilament Proteins - metabolism; Models, Molecular; Molecular Sequence Data; NIH 3T3 Cells; Nuclear Magnetic Resonance, Biomolecular; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Recombinant Fusion Proteins - chemistry; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Reproducibility of Results; Sequence Homology, Amino Acid; SIGNALING; Talin - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2006.01.011

The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Filamins are large, actin-crosslinking proteins that connect multiple transmembrane and signaling proteins to the cytoskeleton. Here, we describe the high-resolution structure of an interface between filamin A and an integrin adhesion receptor. When bound, the integrin β cytoplasmic tail forms an extended β strand that interacts with β strands C and D of the filamin immunoglobulin-like domain (IgFLN) 21. This interface is common to many integrins, and we suggest it is a prototype for other IgFLN domain interactions. Notably, the structurally defined filamin binding site overlaps with that of the integrin-regulator talin, and these proteins compete for binding to integrin tails, allowing integrin-filamin interactions to impact talin-dependent integrin activation. Phosphothreonine-mimicking mutations inhibit filamin, but not talin, binding, indicating that kinases may modulate this competition and provide additional means to control integrin functions.