DAMAGE, a novel alpha-dystrobrevin-associated MAGE protein in dystrophin complexes.
Mice rendered null for alpha-dystrobrevin, a component of the dystrophin complex, have muscular dystrophy, despite the fact that the sarcolemma remains relatively intact (Grady, R. M., Grange, R. W., Lau, K. S., Maimone, M. M., Nichol, M. C., Stull, J. T., and Sanes, J. R. (1999) Nat. Cell Biol. 1, 215-220) Thus, alpha-dystrobrevin may serve a signaling function that is important for the maintenance of muscle integrity. We have identified a new dystrobrevin-associated protein, DAMAGE, that may play a signaling role in brain, muscle, and peripheral nerve. In humans, DAMAGE is encoded by an intronless gene located at chromosome Xq13.1, a locus that contains genes involved in mental retardation. DAMAGE associates directly with alpha-dystrobrevin, as shown by yeast two-hybrid, and co-immunoprecipitates with the dystrobrevin-syntrophin complex from brain. This co-immunoprecipitation is dependent on the presence of alpha-dystrobrevin but not beta-dystrobrevin. The DAMAGE protein contains a potential nuclear localization signal, 30 12-amino acid repeats, and two MAGE homology domains. The domain structure of DAMAGE is similar to that of NRAGE, a MAGE protein that mediates p75 neurotrophin receptor signaling and neuronal apoptosis (Salehi, A. H., Roux, P. P., Kubu, C. J., Zeindler, C., Bhakar, A., Tannis, L. L., Verdi, J. M., and Barker, P. A. (2000) Neuron 27, 279-288). DAMAGE is highly expressed in brain and is present in the cell bodies and dendrites of hippocampal and Purkinje neurons. In skeletal muscle, DAMAGE is at the postsynaptic membrane and is associated with a subset of myonuclei. DAMAGE is also expressed in peripheral nerve, where it localizes along with other members of the dystrophin complex to the perineurium and myelin. These results expand the role of dystrobrevin and the dystrophin complex in membrane signaling and disease.
Albrecht
Douglas E
DE
Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195-7290, USA.
Froehner
Stanley C
SC
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000737:chemistry* / Q000235:genetics; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D016189:Dystrophin / Q000737:chemistry*; D049029:Dystrophin-Associated Proteins; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D008251:Macaca; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009186:Myelin Sheath / Q000737:chemistry; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D019913:Nuclear Localization Signals; D017933:Peripheral Nervous System / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D014162:Transfection; D020798:Two-Hybrid System Techniques; D014960:X Chromosome; D009687:Nuclear Proteins
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004247:DNA; D018076:DNA, Complementary; D016189:Dystrophin; D049029:Dystrophin-Associated Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; C484328:MAGEE1 protein, human; D009687:Nuclear Proteins; C098885:dystrobrevin