Laboratory for Structural Biology Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD
Section on Translational Research for Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD.
J Cell Biol. 2019 Mar 4;218(3):1027-1038. doi: 10.1083/jcb.201806148. Epub 2019 Jan 10.
Mutations in the retinal protein retinoschisin (RS1) cause progressive loss of vision in young males, a form of macular degeneration called X-linked retinoschisis (XLRS). We previously solved the structure of RS1, a 16-mer composed of paired back-to-back octameric rings. Here, we show by cryo-electron microscopy that RS1 16-mers can assemble into extensive branched networks. We classified the different configurations, finding four types of interaction between the RS1 molecules. The predominant configuration is a linear strand with a wavy appearance. Three less frequent types constitute the branch points of the network. In all cases, the "spikes" around the periphery of the double rings are involved in these interactions. In the linear strand, a loop (usually referred to as spike 1) occurs on both sides of the interface between neighboring molecules. Mutations in this loop suppress secretion, indicating the possibility of intracellular higher-order assembly. These observations suggest that branched networks of RS1 may play a stabilizing role in maintaining the integrity of the retina.
视网膜蛋白 retinoschisin (RS1) 的突变导致年轻男性视力逐渐丧失，这是一种称为 X 连锁性视网膜劈裂症 (XLRS) 的黄斑变性形式。我们之前已经解决了 RS1 的结构，它是由成对的背靠背八聚体环组成的 16 元。在这里，我们通过低温电子显微镜显示 RS1 16 元可以组装成广泛的分支网络。我们对不同的构型进行了分类，发现 RS1 分子之间存在四种相互作用类型。主要构型是具有波浪外观的线性链。三种不太常见的类型构成了网络的分支点。在所有情况下，双环外围的“刺”都参与了这些相互作用。在线性链中，在相邻分子之间的界面的两侧都出现一个环（通常称为刺 1）。该环中的突变抑制了分泌，表明可能存在细胞内的高级组装。这些观察结果表明，RS1 的分支网络可能在维持视网膜完整性方面发挥稳定作用。
