Institute of Structural Biology, Helmholtz Zentrum München, Neuherberg, Germany.
Nat Struct Mol Biol. 2011 Nov 20;18(12):1414-20. doi: 10.1038/nsmb.2185.
Arginine dimethylation plays critical roles in the assembly of ribonucleoprotein complexes in pre-mRNA splicing and piRNA pathways. We report solution structures of SMN and SPF30 Tudor domains bound to symmetric and asymmetric dimethylated arginine (DMA) that is inherent in the RNP complexes. An aromatic cage in the Tudor domain mediates dimethylarginine recognition by electrostatic stabilization through cation-π interactions. Distinct from extended Tudor domains, dimethylarginine binding by the SMN and SPF30 Tudor domains is independent of proximal residues in the ligand. Yet, enhanced micromolar affinities are obtained by external cooperativity when multiple methylation marks are presented in arginine- and glycine-rich peptide ligands. A hydrogen bond network in the SMN Tudor domain, including Glu134 and a tyrosine hydroxyl of the aromatic cage, enhances cation-π interactions and is impaired by a mutation causing an E134K substitution associated with spinal muscular atrophy. Our structural analysis enables the design of an optimized binding pocket and the prediction of DMA binding properties of Tudor domains.
精氨酸二甲基化在 pre-mRNA 剪接和 piRNA 通路中的核糖核蛋白复合物组装中发挥着关键作用。我们报告了 SMN 和 SPF30 Tudor 结构域与固有在 RNP 复合物中的对称和非对称二甲基精氨酸 (DMA) 结合的溶液结构。Tudor 结构域中的芳香族笼通过阳离子-π 相互作用通过静电稳定化来介导二甲基精氨酸识别。与扩展的 Tudor 结构域不同，SMN 和 SPF30 Tudor 结构域对配体中近端残基的结合是独立的。然而，当精氨酸和甘氨酸丰富肽配体中存在多个甲基化标记时，通过外部协同作用获得了增强的微摩尔亲和力。SMN Tudor 结构域中的氢键网络，包括 Glu134 和芳香族笼的酪氨酸羟基，增强了阳离子-π 相互作用，并因导致与脊髓性肌萎缩相关的 E134K 取代的突变而受损。我们的结构分析能够设计优化的结合口袋，并预测 Tudor 结构域的 DMA 结合特性。
