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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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The WW Domain of Dystrophin Requires EF-Hands Region to Interact with β-Dystroglycan

S. Rentschler / H. Linn / K. Deininger / M.T. Bedford / X. Espanel / M. Sudol

Citation Information: Biological Chemistry. Volume 380, Issue 4, Pages 431–442, ISSN (Print) 1431-6730, DOI: 10.1515/BC.1999.057, June 2005

Publication History

Published Online:
2005-06-01

Abstract

Skeletal muscle dystrophin is a 427 kDa protein thought to act as a link between the actin cytoskeleton and the extracellular matrix. Perturbations of the dystrophin-associated complex, for example, between dystrophin and the transmembrane glycoprotein β-dystroglycan, may lead to muscular dystrophy. Previously, the cysteine-rich region and first half of the carboxy-terminal domain of dystrophin were shown to interact with β-dystroglycan through a stretch of fifteen amino acids at the carboxy-terminus of β-dystroglycan. This region of dystrophin implicated in binding β-dystroglycan contains four modular protein domains: a WW domain, two putative Ca2+-binding EF-hand motifs, and a putative zinc finger ZZ domain. The WW domain is a globular domain of 38–40 amino acids with two highly conserved tryptophan residues spaced 20–22 amino acids apart. A subset of WW domains was shown to bind ligands that contain a Pro-Pro-x-Tyr core motif (where x is any amino acid). Here we elucidate the role of the WW domain of dystrophin and surrounding sequence in binding β-dystroglycan. We show that the WW domain of dystrophin along with the EF-hand motifs binds to the carboxy-terminus of β-dystroglycan. Through site-specific mutagenesis and in vitro binding assays, we demonstrate that binding of dystrophin to the carboxyterminus of β-dystroglycan occurs via a β-dystroglycan Pro-Pro-x-Tyr core motif. Targeted mutagenesis of conserved WW domain residues reveals that the dystrophin/β-dystroglycan interaction occurs primarily through the WW domain of dystrophin. Precise mapping of this interaction could aid in therapeutic design.

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