Human Molecular Genetics Advance Access published online on February 12, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh087
© 2004 by Oxford University Press
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1 Department of Cell Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi-chou, Kodaira, Tokyo 187-8502, Japan
* To whom correspondence should be addressed. E-mail: ozawa{at}ncnp.go.jp.
An intracellular protein, dystrophin, plays an important role in keeping muscle fibers intact by binding at its N-terminal end to the subsarcolemmal cytoskeletal actin network and via its C-terminal end to the transmembraneous protein
Article
ZZ domain is essentially required for the physiological binding of dystrophin and utrophin to
-dystroglycan
2 MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, United Kingdom
Abstract 
-dystroglycan. Duchenne muscular dystrophy is caused by the loss of dystrophin which can result from the loss of either of this binding. The N-terminal part of the latter binding site of dystrophin has been well documented using overlay assay and X-ray diffraction assays. However, the binding site at the C-terminal region of dystrophin has not been examined in detail. In the present work, we report a detailed analysis of the C-terminal binding domain and we found: (1) The full binding activity corresponding to the effective binding in vivo is expressed by the dystrophin fragment spanning amino acids 3026-3345 containing the ZZ domain at the C-terminus. Determination of this binding range is important not only for understanding of the mechanism of dystrophy, but also useful for the design of truncated dystrophin constructs for gene therapy. (2) The ZZ domain binds to EF1 domain in the dystrophin fragment to reinforce the binding activity. (3) The cysteine #3340 in the ZZ domain is essential for the binding of dystrophin to -dystroglycan. A reported case of DMD due to missense mutation C3340Y may be caused by inability to fix dystrophin beneath the cell membrane. (4) The binding mode of utrophin is different from that of dystrophin. The difference is conspicuous concerning the cysteine residues present in the ZZ domain.
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