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 结合蛋白的低复杂性 (LC) 结构域以导致与水环境相分离的方式自结合。在生理正常的盐和 pH 条件下孵育 FUS LC 结构域会导致快速形成液体状液滴，这些液滴会成熟为凝胶状状态。相分离的两个例子都使还原论生化测定成为可能，从而允许发现 57 个残基的 N 末端区域，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 末端区域的证据，该区域也形成特定的交叉β相互作用。我们建议 FUS LC 域的生物学功能可以通过这些 N 端和 C 端交叉β核心的互斥使用来运作。