Isolated pseudo-RNA-recognition motifs of SR proteins can regulate splicing using a noncanonical mode of RNA recognition
Isolated pseudo-RNA-recognition motifs of SR proteins can regulate splicing using a noncanonical mode of RNA recognition
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DOI：
10.1073/pnas.1303445110
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发表时间：
2013-07-23
影响因子：
11.1
通讯作者：
Allain, Frederic H. -T.
中科院分区：
文献类型：
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作者：
Clery, Antoine;Sinha, Rahul;Allain, Frederic H. -T.
丝氨酸/精氨酸（SR）蛋白是真核生物中选择性剪接调节因子的主要家族之一，具有两种类型的RNA识别基序（RRM）：典型RRM和伪RRM。尽管伪RRM对SR蛋白的活性至关重要，但其作用模式尚不清楚。通过解决与RNA结合的人SRSF 1假RRM的结构，我们发现了一种非常不寻常的序列特异性RNA结合模式，该模式以一个α-螺旋为中心，不涉及通常介导RRM与RNA结合的β-折叠表面。值得注意的是，这种结合模式在所有测试的伪RRM中是保守的。此外，分离的假RRM足以调节约一半的SRSF 1靶基因的剪接，并且结合的α-螺旋是该功能的关键元件。我们的研究结果强烈表明，SR蛋白与伪RRM经常调节剪接竞争，而不是招募，剪接体组件，仅使用这种不寻常的RRM。
Serine/arginine (SR) proteins, one of the major families of alternative-splicing regulators in Eukarya, have two types of RNA-recognition motifs (RRMs): a canonical RRM and a pseudo-RRM. Although pseudo-RRMs are crucial for activity of SR proteins, their mode of action was unknown. By solving the structure of the human SRSF1 pseudo-RRM bound to RNA, we discovered a very unusual and sequence-specific RNA-binding mode that is centered on one alpha-helix and does not involve the beta-sheet surface, which typically mediates RNA binding by RRMs. Remarkably, this mode of binding is conserved in all pseudo-RRMs tested. Furthermore, the isolated pseudo-RRM is sufficient to regulate splicing of about half of the SRSF1 target genes tested, and the bound alpha-helix is a pivotal element for this function. Our results strongly suggest that SR proteins with a pseudo-RRM frequently regulate splicing by competing with, rather than recruiting, spliceosome components, using solely this unusual RRM.