Human Molecular Genetics Advance Access originally published online on February 12, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 7 693-702
DOI: 10.1093/hmg/ddh087
ZZ domain is essentially required for the physiological binding of dystrophin and utrophin to ß-dystroglycan
1Department of Cell Biology, National Institute of Neuroscience, NCNP, 4-1-1 Ogawahigashi-chou, Kodaira, Tokyo 187-8502, Japan and 2MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
Received November 13, 2004; Accepted February 2, 2004
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 ß-dystroglycan. Duchenne muscular dystrophy is caused by the loss of dystrophin, which can result from the loss 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 as follows. (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 ß-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.
* To whom correspondence should be addressed. Tel: +81 423412712 ext. 5266; Fax: +81 423461741; Email: ozawa{at}ncnp.go.jp
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