Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK.
Sci Rep. 2017 Jul 24;7(1):6312. doi: 10.1038/s41598-017-06395-6.
The Cardiomyopathy-associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)-related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for a number of diseases affecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn. Cmya5 and Fsd2 appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on different chromosomes. Using immunoaffinity purification and mass spectrometry we show that minispryn co-purifies with myospryn and the major cardiac ryanodine receptor (RyR2) from heart. Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cells whereas minispryn lacks this activity. Together these data suggest a novel role for the myospryn complex in the assembly of ryanodine receptor clusters in striated muscle.
肌球蛋白相关基因 5 (Cmya5) 编码肌联蛋白(myospryn)，这是一种主要存在于心脏和骨骼肌中的三部分基序 (TRIM) 相关蛋白。Cmya5 是许多影响横纹肌的疾病的表达生物标志物，也可能是精神分裂症的风险基因。为了进一步了解肌联蛋白在横纹肌中的功能，我们寻找了其他肌联蛋白的同源物。在这里，我们鉴定了一种新的肌肉表达的 TRIM 相关蛋白 minispryn，它由 Fsd2 编码，与肌联蛋白的 C 端具有广泛的序列相似性。Cmya5 和 Fsd2 似乎是由染色体重复产生的，并且位于不同染色体上进化保守的基因簇内。使用免疫亲和纯化和质谱法，我们表明 minispryn 与肌联蛋白和心脏中的主要肌质网 Ca2+ 释放通道 (RyR2) 从心脏中共同纯化。因此，肌联蛋白、minispryn 和 RyR2 在分离的心肌细胞的连接肌质网共定位。当在异源细胞中共表达时，肌联蛋白将 RyR2 重新分布到簇中，而 minispryn 则缺乏这种活性。这些数据表明肌联蛋白复合物在横纹肌中肌质网 Ca2+ 释放通道簇的组装中具有新的作用。
