DAMAGE, a Novel α-Dystrobrevin-associated MAGE Protein in Dystrophin Complexes

Douglas E Albrecht,Stanley C Froehner

doi:10.1074/jbc.m312205200

Douglas E Albrecht, Stanley C Froehner

Open Access

https://doi.org/10.1074/jbc.m312205200

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Abstract

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.

Highlights

Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins
We identified an X-chromosome-encoded protein that contains two melanoma-associated antigens (MAGE) homology domains (MHD)1 and multiple 12-amino acid repeats, which we have named DAMAGE
DAMAGE appears to be encoded by an intronless gene

Summary

Introduction

Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. In an effort to identify new ␣-dystrobrevin-interacting proteins, we used the yeast two-hybrid system to screen a mouse cDNA library By using this approach, we identified an X-chromosome-encoded protein that contains two MAGE homology domains (MHD) and multiple 12-amino acid repeats, which we have named DAMAGE (dystrobrevin-associated MAGE protein). We identified an X-chromosome-encoded protein that contains two MAGE homology domains (MHD) and multiple 12-amino acid repeats, which we have named DAMAGE (dystrobrevin-associated MAGE protein) The presence of this protein in neurons, at the neuromuscular junction, in perinuclear structures in skeletal muscle, and in myelin and perineurium of peripheral nerve expands the possible role of ␣-dystrobrevin and the dystrophin complex in membrane signaling and disease

Results

Discussion

Conclusion