Abstract
Dystrophin and β-dystroglycan are components of the dystrophin–glycoprotein complex (DGC), a multimolecular assembly that spans the cell membrane and links the actin cytoskeleton to the extracellular basal lamina. Defects in the dystrophin gene are the cause of Duchenne and Becker muscular dystrophies. The C-terminal region of dystrophin binds the cytoplasmic tail of β-dystroglycan, in part through the interaction of its WW domain with a proline-rich motif in the tail of β-dystroglycan. Here we report the crystal structure of this portion of dystrophin in complex with the proline-rich binding site in β-dystroglycan. The structure shows that the dystrophin WW domain is embedded in an adjacent helical region that contains two EF-hand-like domains. The β-dystroglycan peptide binds a composite surface formed by the WW domain and one of these EF-hands. Additionally, the structure reveals striking similarities in the mechanisms of proline recognition employed by WW domains and SH3 domains.
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Acknowledgements
The authors thank C. Dahl for synthesis and purification of the β-dystroglycan peptide and A. Farooq for help with microcalorimetry measurements. We thank M. Macias for coordinates of the Yap WW domain and for helpful discussions in comparing the structures. This work was supported in part by grants from the NIH (to M.S.), the Muscular Dystrophy Association (to M.J.E. and M.S.), and by the US Department of Energy, Office of Biological and Environmental Research (to A.J. and Rg.Z). M.J.E. is a recipient of a Burroughs-Wellcome Career award in the Biomedical Sciences, and a member of the Harvard-Armenise Center for Structural Biology. Diffraction data were recorded at the Advanced Photon Source at Argonne National Labs, and at CHESS, which is supported by grants from the NIH and NSF.
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Huang, X., Poy, F., Zhang, R. et al. Structure of a WW domain containing fragment of dystrophin in complex with β-dystroglycan. Nat Struct Mol Biol 7, 634–638 (2000). https://doi.org/10.1038/77923
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DOI: https://doi.org/10.1038/77923
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