Durham Jennifer T, Brand Ondra M, Arnold Michael, Reynolds Joseph G, Muthukumar Lavanya, Weiler Hartmut, Richardson James A, Naya Francisco J
Department of Biology, Program in Cell and Molecular Biology, Boston University, Boston, Massachusetts 02215, USA.
J Biol Chem. 2006 Mar 10;281(10):6841-9. doi: 10.1074/jbc.M510499200. Epub 2006 Jan 3.
The full repertoire of proteins that comprise the striated muscle Z-disc and peripheral structures, such as the costamere, have yet to be discovered. Recent studies suggest that this elaborate protein network, which acts as a structural and signaling center for striated muscle, harbors factors that function as mechanosensors to ensure coordinated contractile activity. Mutations in genes whose products reside in this region often result in skeletal and cardio myopathies, demonstrating the importance of this macromolecular complex in muscle structure and function. Here, we describe the characterization of a direct, downstream target gene for the MEF2A transcription factor encoding a large, muscle-specific protein that localizes to the costamere in striated muscle. This gene, called myospryn, was identified by microarray analysis as a transcript down-regulated in MEF2A knock-out mice. MEF2A knock-out mice develop cardiac failure during the perinatal period with mutant hearts exhibiting several cardiac abnormalities including myofibrillar disarray. Myospryn is the mouse ortholog of a partial human cDNA of unknown function named cardiomyopathy-associated gene 5 (CMYA5). Myospryn is expressed as a single, large transcript of approximately 12 kilobases in adult heart and skeletal muscle with an open reading frame of 3739 amino acids. This protein, belonging to the tripartite motif superfamily of proteins, contains a B-box coiled-coil (BBC), two fibronectin type III (FN3) repeats, and SPRY domains and interacts with the sarcomeric Z-disc protein, alpha-actinin-2. Our findings demonstrate that myospryn functions directly downstream of MEF2A at the costamere in striated muscle potentially playing a role in myofibrillogenesis.
构成横纹肌Z盘和外周结构（如肌小节）的全部蛋白质尚未被发现。最近的研究表明，这个复杂的蛋白质网络作为横纹肌的结构和信号中心，含有作为机械传感器发挥作用以确保协调收缩活动的因子。其产物位于该区域的基因突变通常会导致骨骼肌和心肌病，这表明这种大分子复合物在肌肉结构和功能中的重要性。在这里，我们描述了MEF2A转录因子的一个直接下游靶基因的特征，该基因编码一种大的、肌肉特异性蛋白，定位于横纹肌的肌小节。这个名为肌联蛋白的基因通过微阵列分析被鉴定为在MEF2A基因敲除小鼠中下调的转录本。MEF2A基因敲除小鼠在围产期会发生心力衰竭，突变心脏表现出几种心脏异常，包括肌原纤维紊乱。肌联蛋白是人类一个功能未知的部分cDNA（名为心肌病相关基因-5，CMYA5）的小鼠同源物。肌联蛋白在成年心脏和骨骼肌中表达为一个约12千碱基的单一大型转录本，开放阅读框为3739个氨基酸。这种蛋白质属于蛋白质的三联基序超家族，包含一个B盒卷曲螺旋（BBC）、两个纤连蛋白III型（FN3）重复序列和SPRY结构域，并与肌节Z盘蛋白α-辅肌动蛋白-2相互作用。我们的研究结果表明，肌联蛋白在横纹肌的肌小节中直接在MEF2A的下游发挥作用，可能在肌原纤维形成中起作用。
