Graduate Group in Biochemistry and Molecular Biophysics, University of Pennsylvania, Philadelphia, PA 19104, USA.
Structure. 2012 Nov 7;20(11):1929-39. doi: 10.1016/j.str.2012.08.024. Epub 2012 Sep 27.
The survival motor neuron (SMN) protein forms the oligomeric core of a multiprotein complex that functions in spliceosomal snRNP biogenesis. Loss of function mutations in the SMN gene cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. Nearly half of the known SMA patient missense mutations map to the SMN YG-box, a highly conserved oligomerization domain of unknown structure that contains a (YxxG)₃ motif. Here, we report that the SMN YG-box forms helical oligomers similar to the glycine zippers found in transmembrane channel proteins. A network of tyrosine-glycine packing between helices drives formation of soluble YG-box oligomers, providing a structural basis for understanding SMN oligomerization and for relating defects in oligomerization to the mutations found in SMA patients. These results have important implications for advancing our understanding of SMN function and glycine zipper-mediated helix-helix interactions.
运动神经元存活蛋白（SMN）形成了剪接体 snRNP 生物发生中多蛋白复合物的寡聚核心。SMN 基因的功能丧失突变导致脊髓性肌萎缩症（SMA），这是婴儿死亡的主要遗传原因。近一半已知的 SMA 患者错义突变位于 SMN YG 盒，这是一个高度保守的未知结构的寡聚化结构域，其中包含一个（YxxG）₃ 基序。在这里，我们报告 SMN YG 盒形成类似于跨膜通道蛋白中发现的甘氨酸拉链的螺旋寡聚体。螺旋之间的酪氨酸-甘氨酸包装网络驱动可溶性 YG 盒寡聚体的形成，为理解 SMN 寡聚化以及将寡聚化缺陷与在 SMA 患者中发现的突变联系起来提供了结构基础。这些结果对推进我们对 SMN 功能和甘氨酸拉链介导的螺旋-螺旋相互作用的理解具有重要意义。
