A cyclophilin functions in pre-mRNA splicing
A cyclophilin functions in pre-mRNA splicing
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DOI：
10.1093/emboj/21.3.470
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发表时间：
2002-02-01
期刊：
影响因子：
11.4
通讯作者：
Misteli, T
中科院分区：
文献类型：
--
作者：
Horowitz, DS;Lee, EJ;Misteli, T
我们报告，亲环素USA-CyP是不同的复合物的一部分，两个spliceosomal蛋白质，并参与前mRNA剪接的两个步骤。剪接因子hPrp 18和hPrp 4具有短的同源区域，其在每个蛋白质中限定了USA-CyP的高亲和力结合位点。USA-CyP与hPrp 18和hPrp 4形成单独的稳定复合物，其中亲环蛋白的活性位点暴露。亲环素抑制剂环孢菌素A减缓前体mRNA在体外的剪接，我们表明，它的剪接的第二步的抑制是通过阻断其与hPrp 18复合物内的USA-CyP的作用。环孢菌素A也减缓剪接在体内，我们表明，这种减缓的结果，特别是从抑制USA-CyP。我们的研究结果导致一个模型，其中USA-CyP进行到剪接体与hPrp 4和hPrp 18的复合物，和USA-CyP的行为在这些复合物内的剪接。这些结果提供了亲环素在复杂过程中的功能的例子，并提供了亲环素的作用机制的见解。
We report that the cyclophilin USA-CyP is part of distinct complexes with two spliceosomal proteins and is involved in both steps of pre-mRNA splicing. The splicing factors hPrp18 and hPrp4 have a short region of homology that defines a high affinity binding site for USA-CyP in each protein. USA-CyP forms separate, stable complexes with hPrp18 and hPrp4 in which the active site of the cyclophilin is exposed. The cyclophilin inhibitor cyclosporin A slows pre-mRNA splicing in vitro, and we show that its inhibition of the second step of splicing is caused by blocking the action of USA-CyP within its complex with hPrp18. Cyclosporin A also slows splicing in vivo, and we show that this slowing results specifically from inhibition of USA-CyP. Our results lead to a model in which USA-CyP is carried into the spliceosome in complexes with hPrp4 and hPrp18, and USA-CyP acts during splicing within these complexes. These results provide an example of the function of a cyclophilin in a complex process and provide insight into the mechanisms of action of cyclophilins.