Interaction of Muscle and Brain Sodium Channels with Multiple Members of the Syntrophin Family of Dystrophin-Associated Proteins
Interaction of Muscle and Brain Sodium Channels with Multiple Members of the Syntrophin Family of Dystrophin-Associated Proteins
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DOI：
10.1523/jneurosci.18-01-00128.1998
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发表时间：
1998-01
期刊：
影响因子：
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通讯作者：
S. Gee;R. Madhavan;S. Levinson;J. Caldwell;R. Sealock;S. Froehner
中科院分区：
文献类型：
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作者：
S. Gee;R. Madhavan;S. Levinson;J. Caldwell;R. Sealock;S. Froehner
肌营养蛋白是肌营养不良蛋白相关蛋白复合物（DAPC）的细胞质外周膜蛋白。三种突触营养蛋白亚型α1、β1和β2由不同的基因编码。每个包含两个普列克底物蛋白同源（PH）结构域、一个突触营养蛋白独特（SU）结构域和一个PDZ结构域。PDZ这个名字来自于最早发现的三种含有该结构域重复序列的蛋白质（PSD-95、果蝇盘大蛋白和果蝇闭合蛋白1）。其他蛋白质中的PDZ结构域结合到含有共有序列（S/T）XV-COOH的离子通道和神经递质受体的C末端，并介导这些蛋白质的聚集或突触定位。两个电压门控钠通道（NaChs），SkM 1和SkM 2，骨骼肌和心肌，分别有这个共识序列。因为NaChs是肌膜成分，如syntrophins，我们已经研究了这些蛋白质之间可能的相互作用。NaChs与来自骨骼肌和心肌提取物的突触营养蛋白和肌营养不良蛋白共纯化。对应于SkM 1和SkM 2的C-末端10个氨基酸的肽足以结合去污剂溶解的肌肉促突触蛋白，抑制天然NaChs与促突触蛋白PDZ结构域融合蛋白的结合，并特异性结合来自α1-、β1-和β2-促突触蛋白的PDZ结构域。这些肽还抑制促突触蛋白PDZ结构域与神经元型一氧化氮合酶的PDZ结构域的结合，这种相互作用不由C末端序列介导。缺乏（S/T）XV共有序列的脑NaChs也与syntrophin和dystrophin共纯化，这种相互作用似乎不受syntrophin的PDZ结构域介导。总的来说，我们的数据表明，syntrophins连接NaChs的肌动蛋白细胞骨架和细胞外基质通过肌营养不良蛋白和DAPC。
Syntrophins are cytoplasmic peripheral membrane proteins of the dystrophin-associated protein complex (DAPC). Three syntrophin isoforms, α1, β1, and β2, are encoded by distinct genes. Each contains two pleckstrin homology (PH) domains, a syntrophin-unique (SU) domain, and a PDZ domain. The name PDZ comes from the first three proteins found to contain repeats of this domain (PSD-95,Drosophila discs large protein, and the zona occludens protein 1). PDZ domains in other proteins bind to the C termini of ion channels and neurotransmitter receptors containing the consensus sequence (S/T)XV-COOH and mediate the clustering or synaptic localization of these proteins. Two voltage-gated sodium channels (NaChs), SkM1 and SkM2, of skeletal and cardiac muscle, respectively, have this consensus sequence. Because NaChs are sarcolemmal components like syntrophins, we have investigated possible interactions between these proteins. NaChs copurify with syntrophin and dystrophin from extracts of skeletal and cardiac muscle. Peptides corresponding to the C-terminal 10 amino acids of SkM1 and SkM2 are sufficient to bind detergent-solubilized muscle syntrophins, to inhibit the binding of native NaChs to syntrophin PDZ domain fusion proteins, and to bind specifically to PDZ domains from α1-, β1-, and β2-syntrophin. These peptides also inhibit binding of the syntrophin PDZ domain to the PDZ domain of neuronal nitric oxide synthase, an interaction that is not mediated by C-terminal sequences. Brain NaChs, which lack the (S/T)XV consensus sequence, also copurify with syntrophin and dystrophin, an interaction that does not appear to be mediated by the PDZ domain of syntrophin. Collectively, our data suggest that syntrophins link NaChs to the actin cytoskeleton and the extracellular matrix via dystrophin and the DAPC.