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The WW domain of dystrophin requires EF-hands region to interact with beta-dystroglycan.

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 beta-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 beta-dystroglycan through a stretch of fifteen amino acids at the carboxy-terminus of beta-dystroglycan. This region of dystrophin implicated in binding beta-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 beta-dystroglycan. We show that the WW domain of dystrophin along with the EF-hand motifs binds to the carboxy-terminus of beta-dystroglycan. Through site-specific mutagenesis and in vitro binding assays, we demonstrate that binding of dystrophin to the carboxy-terminus of beta-dystroglycan occurs via a beta-dystroglycan Pro-Pro-x-Tyr core motif. Targeted mutagenesis of conserved WW domain residues reveals that the dystrophin/beta-dystroglycan interaction occurs primarily through the WW domain of dystrophin. Precise mapping of this interaction could aid in therapeutic design.

Pubmed ID: 10355629

Authors

  • Rentschler S
  • Linn H
  • Deininger K
  • Bedford MT
  • Espanel X
  • Sudol M

Journal

Biological chemistry

Publication Data

April 2, 1999

Associated Grants

  • Agency: NCI NIH HHS, Id: CA01605
  • Agency: NCI NIH HHS, Id: CA45745
  • Agency: NIDDK NIH HHS, Id: DK50795

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Cytoskeletal Proteins
  • DNA Primers
  • Dystroglycans
  • Dystrophin
  • Humans
  • Membrane Glycoproteins
  • Mice
  • Molecular Sequence Data
  • Precipitin Tests
  • Protein Binding
  • Recombinant Fusion Proteins