Research Group Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Research Group Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany; Max Planck Research Group Nucleic Acid Chemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany.
Mol Cell. 2016 Oct 20;64(2):307-319. doi: 10.1016/j.molcel.2016.08.036. Epub 2016 Oct 6.
SF3b is a heptameric protein complex of the U2 small nuclear ribonucleoprotein (snRNP) that is essential for pre-mRNA splicing. Mutations in the largest SF3b subunit, SF3B1/SF3b155, are linked to cancer and lead to alternative branch site (BS) selection. Here we report the crystal structure of a human SF3b core complex, revealing how the distinctive conformation of SF3b155's HEAT domain is maintained by multiple contacts with SF3b130, SF3b10, and SF3b14b. Protein-protein crosslinking enabled the localization of the BS-binding proteins p14 and U2AF65 within SF3b155's HEAT-repeat superhelix, which together with SF3b14b forms a composite RNA-binding platform. SF3b155 residues, the mutation of which leads to cancer, contribute to the tertiary structure of the HEAT superhelix and its surface properties in the proximity of p14 and U2AF65. The molecular architecture of SF3b reveals the spatial organization of cancer-related SF3b155 mutations and advances our understanding of their effects on SF3b structure and function.
SF3b 是 U2 小核核糖核蛋白（snRNP）的七聚体蛋白复合物，对前体 mRNA 的剪接至关重要。最大的 SF3b 亚基 SF3B1/SF3b155 中的突变与癌症有关，并导致选择性分支位点（BS）的选择。在这里，我们报告了人 SF3b 核心复合物的晶体结构，揭示了 SF3b155 的 HEAT 结构域的独特构象如何通过与 SF3b130、SF3b10 和 SF3b14b 的多种相互作用得以维持。蛋白质 - 蛋白质交联使 BS 结合蛋白 p14 和 U2AF65 定位于 SF3b155 的 HEAT 重复超螺旋内，该超螺旋与 SF3b14b 一起形成复合 RNA 结合平台。导致癌症的 SF3b155 突变残基有助于 HEAT 超螺旋的三级结构及其在 p14 和 U2AF65 附近的表面特性。SF3b 的分子结构揭示了与癌症相关的 SF3b155 突变的空间组织，并增进了我们对其对 SF3b 结构和功能影响的理解。
