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Title | Structural basis of the filamin A actin-binding domain interaction with F-actin. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 25, Issue 10, Page 918-927, Year 2018 |
Publish date | Sep 17, 2018 |
Authors | Daniel V Iwamoto / Andrew Huehn / Bertrand Simon / Clotilde Huet-Calderwood / Massimiliano Baldassarre / Charles V Sindelar / David A Calderwood / |
PubMed Abstract | 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 ...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. |
External links | Nat Struct Mol Biol / PubMed:30224736 / PubMed Central |
Methods | EM (helical sym.) |
Resolution | 3.54 - 9.8 Å |
Structure data | EMDB-7831, PDB-6d8c: EMDB-7832: EMDB-7833: EMDB-8918: |
Chemicals | ChemComp-ADP: ChemComp-MG: |
Source |
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Keywords | STRUCTURAL PROTEIN / Actin-binding domain / Actin crosslinker |