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

Abstract

Mice rendered null for ␣-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, ␣-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. DAM-AGE associates directly with ␣-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 ␣-dystrobrevin but not ␤-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.The dystrophin glycoprotein complex links the actin cytoskeleton to the extracellular matrix in skeletal muscle. In addition, recent studies (1-7) have shown that the dystrophin complex is critical for the localization of a variety of signaling molecules to the skeletal muscle sarcolemma. Thus, the dystrophin complex functions as both a structural link to the extracellular matrix and as a scaffold that concentrates and stabilizes functionally inter-related signaling proteins at the muscle cell membrane.Part of the signaling function of the dystrophin complex may be mediated by the dystrobrevins. The role of the dystrobrevins in signaling is not fully understood; however, targeted disruption of the ␣-dystrobrevin gene in mice results in muscle pathology without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy (8). These findings suggest that ␣-dystrobrevin is important for muscle function but in a non-structural way. Dystrobrevin has no enzymatic activity of its own; therefore, the involvement of dystrobrevin in signaling pathways is dependent on its interaction with other proteins.The dystrobrevins are transcribed from two separate genes, designated ␣ and ␤, that shar...

Interaction of α-Catulin with Dystrobrevin Contributes to Integrity of Dystrophin Complex in Muscle

“…These diverse isoforms can control specific interactions with different signaling proteins by shuffling specific domains responsible for the interactions. In addition to interactions with dystrophin, syntrophins, and the sarcoglycan complex, ␣-dystrobrevin interacts, through its different domains, with several additional cytoskeletal proteins, including syncoilin (38), synemin (or desmuslin) (39), kinesin heavy chain (40), and DAMAGE (41). Such interactions with a variety of proteins correlate with the observation that the DAPC is broadly localized throughout the sarcolemma, although it is enriched at costameres.…”

Syncoilin is required for generating maximum isometric stress in skeletal muscle but dispensable for muscle cytoarchitecture

“…In addition to the interaction of ␣-dystrobrevin with the DPC components dystrophin, utrophin, and syntrophin (reviewed in Ref. 6), ␣-dystrobrevin has been shown to bind to dysbindin (5), synemin/desmuslin (24), DAMAGE (1), and syncoilin (26) [not to be confused with syncolin, a microtube-associated protein in erythrocytes (16) and syncollin, a secretory granule protein in pancreas and neutrophils (3,13)]. The specific functions of these proteins remain to be elucidated.…”

α-Dystrobrevin distribution and association with other proteins in human promyelocytic NB4 cells treated for granulocytic differentiation

“…Targeted disruption of the -DB gene in mice results, however, in muscular pathology but without the membrane fragility characteristic of dystrophin-deficient muscular dystrophy [3]. These findings suggest that -DB is important for muscle function, perhaps in a non-structural way [4].…”

“…It was, for instance, that -DB can interact with syncoilin, desmuslin, actin, dysbindin and Kif5 [4,6,7].…”