Skip to Main content Skip to Navigation
Journal articles

How the central domain of dystrophin acts to bridge F-actin to sarcolemmal lipids

Abstract : Dystrophin is a large intracellular protein that prevents sarcolemmal ruptures by providing a mechanical link between the intracellular actin cytoskeleton and the transmembrane dystroglycan complex. Dystrophin deficiency leads to the severe muscle wasting disease Duchenne Muscular Dystrophy and the milder allelic variant, Becker Muscular Dystrophy (DMD and BMD). Previous work has shown that concomitant interaction of the actin binding domain 2 (ABD2) comprising spectrin like repeats 11 to 15 (R11-15) of the central domain of dystrophin, with both actin and membrane lipids, can greatly increase membrane stiffness. Based on a combination of SAXS and SANS measurements, mass spectrometry analysis of cross-linked complexes and interactive low-resolution simulations, we explored in vitro the molecular properties of dystrophin that allow the formation of ABD2-F-actin and ABD2-membrane model complexes. In dystrophin we identified two subdomains interacting with F-actin, one located in R11 and a neighbouring region in R12 and another one in R15, while a single lipid binding domain was identified at the C-terminal end of R12. Relative orientations of the dystrophin central domain with F-actin and a membrane model were obtained from docking simulation under experimental constraints. SAXS-based models were then built for an extended central subdomain from R4 to R19, including ABD2. Overall results are compatible with a potential F-actin/dystrophin/membrane lipids ternary complex. Our description of this selected part of the dystrophin associated complex bridging muscle cell membrane and cytoskeleton opens the way to a better understanding of how cell muscle scaffolding is maintained through this essential protein.
Document type :
Journal articles
Complete list of metadatas

Cited literature [54 references]  Display  Hide  Download

https://hal-univ-rennes1.archives-ouvertes.fr/hal-02394326
Contributor : Laurent Jonchère <>
Submitted on : Friday, July 17, 2020 - 10:22:00 AM
Last modification on : Saturday, October 10, 2020 - 3:07:31 AM

File

hal-02394326.pdf
Publication funded by an institution

Licence


Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives 4.0 International License

Identifiers

Citation

Dominique Mias-Lucquin, Raphael dos Santos Morais, Angélique Chéron, Mélanie Lagarrigue, Steve J Winder, et al.. How the central domain of dystrophin acts to bridge F-actin to sarcolemmal lipids. Journal of Structural Biology, Elsevier, 2020, 209 (1), pp.107411. ⟨10.1016/j.jsb.2019.107411⟩. ⟨hal-02394326⟩

Share

Metrics

Record views

136

Files downloads

72