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Nat Struct Mol Biol. 2018 Oct;25(10):918-927. doi: 10.1038/s41594-018-0128-3. Epub 2018 Sep 17.

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

Author information

1
Department of Pharmacology, Yale University, New Haven, CT, USA.
2
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
3
Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
4
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA. charles.sindelar@yale.edu.
5
Department of Pharmacology, Yale University, New Haven, CT, USA. david.calderwood@yale.edu.
6
Department of Cell Biology, Yale University, New Haven, CT, USA. david.calderwood@yale.edu.

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 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.

PMID:
30224736
PMCID:
PMC6173970
[Available on 2019-03-17]
DOI:
10.1038/s41594-018-0128-3

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