Lichtenstein Mauriz A, Cao Fakun, Lobnow Finn, Dirvanskyte Paulina, Weyhenmeyer Daniel, Kulesza Anna, Ziska Elke, Halfmann Randal, Taylor Marcus J
Max Planck Institute for Infection Biology, Berlin, Germany.
Stowers Institute for Medical Research, Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, MO, USA.
Science. 2025 Apr 25;388(6745):415-422. doi: 10.1126/science.adq3234. Epub 2025 Apr 24.
Protein polymer scaffolds composed of death fold (DF) proteins are critical to the formation of signalosomes in immune signaling. The biophysical properties that these polymeric scaffolds require for signal transduction are not clearly defined. Here, we engineered single-component DF signalosomes. We found that functionality depends on the stability provided by the DF polymer, which could also be achieved with a bacterial DF domain, a synthetic filament-forming domain, and amyloid-like sequences. This demonstrates the importance of polymer stability and inducibility irrespective of the motif's origin. By varying the number of included TRAF6 interaction motifs, we demonstrate that avidity is a tunable property that can control the amplitude of signaling outputs. This work lays out a reductionist framework to elucidate the required signaling properties through polymeric scaffolds by adjusting their assembly kinetics, stability, and avidity.
由死亡折叠（DF）蛋白组成的蛋白质聚合物支架对于免疫信号传导中信号小体的形成至关重要。这些聚合物支架进行信号转导所需的生物物理特性尚未明确界定。在此，我们构建了单组分DF信号小体。我们发现其功能取决于DF聚合物提供的稳定性，这种稳定性也可通过细菌DF结构域、合成丝状结构域和淀粉样序列来实现。这证明了聚合物稳定性和可诱导性的重要性，而与基序的来源无关。通过改变所包含的TRAF6相互作用基序的数量，我们证明亲和力是一种可调节的特性，能够控制信号输出的幅度。这项工作构建了一个简化论框架，通过调整聚合物支架的组装动力学、稳定性和亲和力来阐明所需的信号传导特性。
