Institute of Molecular and Cell Biology, Proteos, Singapore 138673, Singapore.
Nucleic Acids Res. 2012 Nov;40(21):11009-22. doi: 10.1093/nar/gks792. Epub 2012 Sep 10.
Mutations in immunoglobulin µ-binding protein 2 (Ighmbp2) cause distal spinal muscular atrophy type 1 (DSMA1), an autosomal recessive disease that is clinically characterized by distal limb weakness and respiratory distress. However, despite extensive studies, the mechanism of disease-causing mutations remains elusive. Here we report the crystal structures of the Ighmbp2 helicase core with and without bound RNA. The structures show that the overall fold of Ighmbp2 is very similar to that of Upf1, a key helicase involved in nonsense-mediated mRNA decay. Similar to Upf1, domains 1B and 1C of Ighmbp2 undergo large conformational changes in response to RNA binding, rotating 30° and 10°, respectively. The RNA binding and ATPase activities of Ighmbp2 are further enhanced by the R3H domain, located just downstream of the helicase core. Mapping of the pathogenic mutations of DSMA1 onto the helicase core structure provides a molecular basis for understanding the disease-causing consequences of Ighmbp2 mutations.
免疫球蛋白 μ 结合蛋白 2（Ighmbp2）突变导致远端脊髓性肌萎缩症 1 型（DSMA1），这是一种常染色体隐性疾病，其临床特征为远端肢体无力和呼吸窘迫。然而，尽管进行了广泛的研究，致病突变的机制仍然难以捉摸。在这里，我们报告了带有和不带有结合 RNA 的 Ighmbp2 解旋酶核心的晶体结构。这些结构表明，Ighmbp2 的整体折叠与参与无意义介导的 mRNA 降解的关键解旋酶 Upf1 非常相似。与 Upf1 相似，Ighmbp2 的结构域 1B 和 1C 在响应 RNA 结合时会发生大的构象变化，分别旋转 30°和 10°。位于解旋酶核心下游的 R3H 结构域进一步增强了 Ighmbp2 的 RNA 结合和 ATP 酶活性。将 DSMA1 的致病性突变映射到解旋酶核心结构上，为理解 Ighmbp2 突变导致疾病的后果提供了分子基础。
