The molecular basis of filamin binding to integrins and competition with talin

Tiila Kiema, Yatish Lad, Pengju Jiang, Camilla L Oxley, Massimiliano Baldassarre, Kate L Wegener, Iain D Campbell, Jari Ylänne, David A Calderwood

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277 Citations (Scopus)

Abstract

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 beta cytoplasmic tail forms an extended beta strand that interacts with beta 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.

Original languageEnglish
Pages (from-to)337-47
Number of pages11
JournalMolecular Cell
Volume21
Issue number3
DOIs
Publication statusPublished - 3 Feb 2006

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Keywords

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calpain
  • Contractile Proteins
  • Crystallography, X-Ray
  • Filamins
  • Integrin beta Chains
  • Mice
  • Microfilament Proteins
  • Models, Molecular
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Recombinant Fusion Proteins
  • Reproducibility of Results
  • Sequence Homology, Amino Acid
  • Talin

Cite this

Kiema, T., Lad, Y., Jiang, P., Oxley, C. L., Baldassarre, M., Wegener, K. L., Campbell, I. D., Ylänne, J., & Calderwood, D. A. (2006). The molecular basis of filamin binding to integrins and competition with talin. Molecular Cell, 21(3), 337-47. https://doi.org/10.1016/j.molcel.2006.01.011