Structural basis of the filamin A actin-binding domain interaction with F-actin

Daniel V. Iwamoto, Andrew Huehn, Bertrand Simon, Clotilde Huet-Calderwood, Massimiliano Baldassarre, Charles V. Sindelar (Corresponding Author), David A. Calderwood (Corresponding Author)

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39 Citations (Scopus)
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Actin-cross-linking proteins assemble actin filaments into higher-order structures essential for orchestrating cell shape, adhesion, and motility. Missense mutations in the tandem calponin homology domains of their actin-binding domains (ABDs) underlie numerous genetic diseases, but a molecular understanding of these pathologies is hampered by the lack of high-resolution structures of any actin-cross-linking protein bound to F-actin. Here, taking advantage of a high-affinity, disease-associated mutant of the human filamin A (FLNa) ABD, we combine cryo-electron microscopy and functional studies to reveal at near-atomic resolution how the first calponin homology domain (CH1) and residues immediately N-terminal to it engage actin. We further show that reorientation of CH2 relative to CH1 is required to avoid clashes with actin and to expose F-actin-binding residues on CH1. Our data explain localization of disease-associated loss-of-function mutations to FLNaCH1 and gain-of-function mutations to the regulatory FLNaCH2. Sequence conservation argues that this provides a general model for ABD–F-actin binding.
Original languageEnglish
Pages (from-to)918-927
Number of pages10
JournalNature Structural & Molecular Biology
Early online date17 Sep 2018
Publication statusPublished - Oct 2018


  • actin
  • cryoelectron microscope


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