DAMAGE, a novel α-dystrobrevin-associated MAGE protein in dystrophin complexes
DAMAGE, a novel α-dystrobrevin-associated MAGE protein in dystrophin complexes
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DOI：
10.1074/jbc.m312205200
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发表时间：
2004-02-20
影响因子：
4.8
通讯作者：
Froehner, SC
中科院分区：
文献类型：
--
作者：
Albrecht, DE;Froehner, SC
抗肌营养不良蛋白复合体的一种成分a-dystrobrevin缺失的小鼠患有肌肉营养不良，尽管肌膜保持相对完整的事实(Grady，R.M.，Grange，R.W.，Lau，K.S.，Maimone，M.M.，Nichol.M.C.，Stull，J.T.，和Sanes，J.R.(1999)NAT。细胞生物。1,215-220)，因此，α-dystrobrevin可能起到对维持肌肉完整性很重要的信号功能。我们已经确定了一种新的营养不良蛋白相关蛋白--损伤，它可能在大脑、肌肉和周围神经中发挥信号作用。在人类中，损伤是由位于染色体Xq13.1上的一个无内含子基因编码的，该基因座包含与智力低下有关的基因。损伤与α-dystrobrevin直接相关，如酵母双杂交所示，并与来自大脑的dystrobrevin-syntroin复合体免疫共沉淀。这种免疫共沉淀依赖于α-dystrobrevin的存在，而不是β-dystrobrevin的存在。该损伤蛋白含有一个潜在的核定位信号、30个12个氨基酸重复序列和两个MAGE同源结构域。损伤的结构域类似于NRAGE，NRAGE是一种MAGE蛋白，介导p75神经营养素受体信号转导和神经元凋亡(Salehi，A.H.，Roux，P.P.，Kubu，C.J.，Zeindler，C.，Bhakar，A.，Tannis，L.，Verdi，J.M.和Barker，P.A.(2000)Neuron 27,279-288)。损伤在脑中高度表达，存在于海马神经元和浦肯野神经元的胞体和树突中。在骨骼肌中，损伤发生在突触后膜，并与肌核的一个子集有关。损伤也表现在周围神经，它与dystrophin复合体的其他成员一起定位于神经膜和髓鞘。这些结果扩大了dystrobrevin和dystrophin复合体在膜信号和疾病中的作用。
Mice rendered null for a-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.