Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390;
Institute for Quantum Life Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan.
Proc Natl Acad Sci U S A. 2021 Oct 19;118(42). doi: 10.1073/pnas.2114412118.
The low-complexity (LC) domain of the fused in sarcoma (FUS) RNA binding protein self-associates in a manner causing phase separation from an aqueous environment. Incubation of the FUS LC domain under physiologically normal conditions of salt and pH leads to rapid formation of liquid-like droplets that mature into a gel-like state. Both examples of phase separation have enabled reductionist biochemical assays allowing discovery of an N-terminal region of 57 residues that assembles into a labile, cross-β structure. Here we provide evidence of a nonoverlapping, C-terminal region of the FUS LC domain that also forms specific cross-β interactions. We propose that biologic function of the FUS LC domain may operate via the mutually exclusive use of these N- and C-terminal cross-β cores. Neurodegenerative disease-causing mutations in the FUS LC domain are shown to imbalance the two cross-β cores, offering an unanticipated concept of LC domain function and dysfunction.
融合肉瘤（FUS）RNA 结合蛋白的低复杂度（LC）结构域以自缔合的方式在水溶液中发生相分离。在生理正常的盐和 pH 条件下孵育 FUS LC 结构域会导致迅速形成液态液滴，然后成熟为凝胶状。这两种相分离的例子都使简化的生化测定成为可能，从而发现了一个由 57 个残基组成的 N 端区域，该区域组装成不稳定的交叉-β 结构。在这里，我们提供了 FUS LC 结构域的非重叠 C 端区域也形成特定的交叉-β 相互作用的证据。我们提出，FUS LC 结构域的生物学功能可能通过这两个 N 端和 C 端交叉-β 核心的相互排斥使用来发挥作用。在 FUS LC 结构域中发现的神经退行性疾病相关突变会使这两个交叉-β 核心失去平衡，为 LC 结构域功能和功能障碍提供了一个意想不到的概念。
