Department of Biochemistry & Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105-6059, USA.
Integrative Program for Biological & Genome Sciences, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Nucleic Acids Res. 2021 Jul 21;49(13):7644-7664. doi: 10.1093/nar/gkab508.
Protein oligomerization is one mechanism by which homogenous solutions can separate into distinct liquid phases, enabling assembly of membraneless organelles. Survival Motor Neuron (SMN) is the eponymous component of a large macromolecular complex that chaperones biogenesis of eukaryotic ribonucleoproteins and localizes to distinct membraneless organelles in both the nucleus and cytoplasm. SMN forms the oligomeric core of this complex, and missense mutations within its YG box domain are known to cause Spinal Muscular Atrophy (SMA). The SMN YG box utilizes a unique variant of the glycine zipper motif to form dimers, but the mechanism of higher-order oligomerization remains unknown. Here, we use a combination of molecular genetic, phylogenetic, biophysical, biochemical and computational approaches to show that formation of higher-order SMN oligomers depends on a set of YG box residues that are not involved in dimerization. Mutation of key residues within this new structural motif restricts assembly of SMN to dimers and causes locomotor dysfunction and viability defects in animal models.
蛋白质寡聚化是均相溶液分离成不同液相的一种机制，使无膜细胞器能够组装。运动神经元存活（SMN）是一个大型大分子复合物的同名成分，该复合物可伴侣真核核糖核蛋白的生物发生，并定位于细胞核和细胞质中的不同无膜细胞器。SMN 构成该复合物的寡聚核心，其 YG 盒结构域内的错义突变已知会导致脊髓性肌萎缩症（SMA）。SMN YG 盒利用甘氨酸拉链模体的独特变体形成二聚体，但高级别寡聚化的机制仍然未知。在这里，我们使用分子遗传学、系统发育学、生物物理学、生物化学和计算方法的组合，表明高级别 SMN 寡聚体的形成取决于一组不参与二聚化的 YG 盒残基。该新结构模体中关键残基的突变将 SMN 的组装限制为二聚体，并导致动物模型中的运动功能障碍和生存能力缺陷。
