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

Nature Structural & Molecular Biology
Daniel V IwamotoDavid A Calderwood

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.

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Citations

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Methods Mentioned

BETA
electron microscopy
X-ray
size-exclusion chromatography
PCR

Software Mentioned

ImageJ
Coot
GraphPad
Prism
BioRad CFX Manager
eLBOW
MotionCor2
Phenix
e2helixboxer
CellProfiler

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