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首页> 外文期刊>Acta crystallographica. Section D, Structural biology >Structural and functional investigation of the human snRNP assembly factor AAR2 in complex with the RNase H-like domain of PRPF8
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Structural and functional investigation of the human snRNP assembly factor AAR2 in complex with the RNase H-like domain of PRPF8

机译：人 snRNP 组装因子 AAR2 与 PRPF8 的 RNase H 样结构域复合物的结构和功能研究

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摘要

Small nuclear ribonucleoprotein complexes (snRNPs) represent the main subunits of the spliceosome. While the assembly of the snRNP core particles has been well characterized, comparably little is known of the incorporation of snRNP-specific proteins and the mechanisms of snRNP recycling. U5 snRNP assembly in yeast requires binding of the the Aar2 protein to Prp8p as a placeholder to preclude premature assembly of the SNRNP200 helicase, but the role of the human AAR2 homolog has not yet been investigated in detail. Here, a crystal structure of human AAR2 in complex with the RNase H-like domain of the U5-specific PRPF8 (PRP8F RH) is reported, revealing a significantly different interaction between the two proteins compared with that in yeast. Based on the structure of the AAR2-PRPF8 RH complex, the importance of the interacting regions and residues was probed and AAR2 variants were designed that failed to stably bind PRPF8 in vitro. Protein-interaction studies of AAR2 with U5 proteins using size-exclusion chromatography reveal similarities and marked differences in the interaction patterns compared with yeast Aar2p and imply phosphorylation-dependent regulation of AAR2 reminiscent of that in yeast. It is found that in vitro AAR2 seems to lock PRPF8 RH in a conformation that is only compatible with the first transesterification step of the splicing reaction and blocks a conformational switch to the step 2-like, Mg2+-coordinated conformation that is likely during U5 snRNP biogenesis. These findings extend the picture of AAR2 PRP8 interaction from yeast to humans and indicate a function for AAR2 in the spliceosomal assembly process beyond its role as an SNRNP200 placeholder in yeast.
机译：小型核核糖核蛋白复合物(snRNPs)代表了剪接体的主要单元。而snRNP核心粒子的组装已经研究的很透彻,相对小吗snRNP-specific合并的蛋白质和snRNP回收的机制。在酵母U5 snRNP装配需要绑定的Aar2蛋白Prp8p作为占位符排除过早SNRNP200的组装解旋酶,但人类AAR2同系物的角色尚未详细调查。人类AAR2在复杂的晶体结构核糖核酸酶的H-like域的U5-specific PRPF8(PRP8F RH)报道,暴露的明显不同的两种蛋白质间的相互作用相比之下,在酵母。AAR2-PRPF8 RH的结构复杂,地区和互动的重要性残留是探测和AAR2变体未能稳定PRPF8结合的设计体外。使用凝胶排阻层析法U5蛋白质揭示相似点和差异交互模式与酵母Aar2p相比和暗示phosphorylation-dependent监管AAR2想起,在酵母。体外AAR2似乎锁PRPF8 RH中只有兼容的构象拼接的酯基转移作用的第一步反应和块构象开关步骤2,Mg2 +协调构象这很可能在U5 snRNP生物转化。发现延长的照片AAR2 PRP8交互从酵母到人类和指示函数的AAR2 spliceosomal组装作为一个SNRNP200过程之外的角色酵母的占位符。

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