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首页> 外文期刊>Molecular and Cellular Biology >Alternative Splicing Controls Myotonic Dystrophy Protein Kinase Structure, Enzymatic Activity, and Subcellular Localization
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Alternative Splicing Controls Myotonic Dystrophy Protein Kinase Structure, Enzymatic Activity, and Subcellular Localization

机译：替代剪接控制强直性营养不良蛋白激酶结构，酶活性和亚细胞定位。

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Transcripts of the myotonic dystrophy protein kinase (DMPK) gene, a member of the Rho kinase family, are subject to cell-type specific alternative splicing. An imbalance in the splice isoform profile of DMPK may play a role in the pathogenesis of DM1, a severe multisystemic disorder. Here, we report how structural subdomains determine biochemical properties and subcellular distribution of DMPK isoforms. A newly developed kinase assay revealed that DMPK is a Lys/Arg-directed kinase. Individual DMPK isoforms displayed comparable transphosphorylation activity and sequence preference for peptide substrates. However, DMPK autophosphorylation and phosphorylation of MYPT1 (as putative in vivo target of DMPK), were dependent on presence of an alternatively spliced VSGGG motif and the nature of the C terminus. In-gel effects of the VSGGG motif on the migration behavior of full-length kinase provide evidence for a model in which this motif mediates 3-D-conformational changes in DMPK isoforms. Finally, different C termini endow DMPK with the ability to bind to either endoplasmic reticulum or mitochondria or to adopt a cytosolic location. Our results suggest that DMPK isoforms have cell-type and location dependent substrate specificities with a role in organellar and cytoarchitectural dynamics.
机译：作为Rho激酶家族成员的强直性肌营养不良蛋白激酶（ DMPK ）基因的转录物需要进行细胞类型的特异性剪接。 DMPK的剪接同工型谱中的失衡可能在DM1（一种严重的多系统性疾病）的发病机理中起作用。在这里，我们报告结构子域如何确定DMPK亚型的生化特性和亚细胞分布。新开发的激酶测定法表明DMPK是Lys / Arg导向的激酶。单个DMPK同工型显示出可比的转磷酸活性和肽底物的序列偏好性。但是，MYPK1（作为DMPK的体内靶标）的DMPK自磷酸化和磷酸化取决于是否存在可变剪接的VSGGG基序和C末端的性质。 VSGGG基序对全长激酶迁移行为的凝胶效应为该基序介导DMPK同工型的3D构象变化提供了模型证据。最后，不同的C末端赋予DMPK结合内质网或线粒体或采用胞质定位的能力。我们的结果表明，DMPK同工型具有细胞类型和位置依赖性底物特异性，并在细胞器和细胞结构动力学中起作用。

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