Institute of Molecular and Cell Biology, 61 Biopolis Drive, Singapore 138673.
Department of Biochemistry and Howard Hughes Medical Institute, University of Colorado, Boulder, Boulder CO 80303, USA.
Cell Res. 2014 Feb;24(2):233-46. doi: 10.1038/cr.2013.152. Epub 2013 Nov 19.
The evolutionarily conserved Lsm1-7-Pat1 complex is the most critical activator of mRNA decapping in eukaryotic cells and plays many roles in normal decay, AU-rich element-mediated decay, and miRNA silencing, yet how Pat1 interacts with the Lsm1-7 complex is unknown. Here, we show that Lsm2 and Lsm3 bridge the interaction between the C-terminus of Pat1 (Pat1C) and the Lsm1-7 complex. The Lsm2-3-Pat1C complex and the Lsm1-7-Pat1C complex stimulate decapping in vitro to a similar extent and exhibit similar RNA-binding preference. The crystal structure of the Lsm2-3-Pat1C complex shows that Pat1C binds to Lsm2-3 to form an asymmetric complex with three Pat1C molecules surrounding a heptameric ring formed by Lsm2-3. Structure-based mutagenesis revealed the importance of Lsm2-3-Pat1C interactions in decapping activation in vivo. Based on the structure of Lsm2-3-Pat1C, a model of Lsm1-7-Pat1 complex is constructed and how RNA binds to this complex is discussed.
进化上保守的 Lsm1-7-Pat1 复合物是真核细胞中 mRNA 去帽的最关键激活因子，在正常衰变、富含 AU 元件介导的衰变和 miRNA 沉默中发挥多种作用，但 Pat1 如何与 Lsm1-7 复合物相互作用尚不清楚。在这里，我们表明 Lsm2 和 Lsm3 桥接 Pat1（Pat1C）的 C 端与 Lsm1-7 复合物之间的相互作用。Lsm2-3-Pat1C 复合物和 Lsm1-7-Pat1C 复合物在体外以相似的程度刺激脱帽，并表现出相似的 RNA 结合偏好。Lsm2-3-Pat1C 复合物的晶体结构表明，Pat1C 结合到 Lsm2-3 上，形成一个不对称的复合物，三个 Pat1C 分子围绕 Lsm2-3 形成的七聚体环。基于结构的突变分析揭示了 Lsm2-3-Pat1C 相互作用在体内脱帽激活中的重要性。基于 Lsm2-3-Pat1C 的结构，构建了 Lsm1-7-Pat1 复合物的模型，并讨论了 RNA 如何与该复合物结合。
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