Kobe Bostjan, Nanson Jeffrey D, Hoad Mikayla, Blumenthal Antje, Gambin Yann, Sierecki Emma, Stacey Katryn J, Ve Thomas, Halfmann Randal
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD 4072, Australia.
Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD 4072, Australia.
Biochem J. 2025 Mar 5;482(5):275-294. doi: 10.1042/BCJ20220094.
The concept of higher-order assembly signalling or signalling by co-operative assembly formation (SCAF) was proposed based on the structures of signalling assemblies formed by proteins featuring domains from the death-fold family and the Toll/interleukin-1 receptor domain family. Because these domains form filamentous assemblies upon stimulation and activate downstream pathways through induced proximity, they were envisioned to sharpen response thresholds through the extreme co-operativity of higher-order assembly. Recent findings demonstrate that a central feature of the SCAF mechanism is the nucleation barrier that allows a switch-like, digital or 'all-or-none' response to minute stimuli. In agreement, this signalling mechanism features in cell-death and innate immunity activation pathways where a binary decision is required. Here, we broaden the concept of SCAF to encapsulate the essential kinetic properties of open-ended assembly in signalling, compare properties of filamentous assemblies and other co-operative assemblies such as biomolecular condensates, and review how this concept operates in cells.
基于由具有死亡折叠家族结构域和Toll/白细胞介素-1受体结构域家族结构域的蛋白质形成的信号组装体的结构，提出了高阶组装信号传导或协同组装形成信号传导（SCAF）的概念。由于这些结构域在受到刺激时会形成丝状组装体，并通过诱导接近激活下游途径，因此人们设想它们通过高阶组装的极端协同作用来提高反应阈值。最近的研究结果表明，SCAF机制的一个核心特征是成核屏障，它允许对微小刺激产生类似开关的、数字式的或“全或无”的反应。与此一致的是，这种信号传导机制在需要二元决策的细胞死亡和先天免疫激活途径中发挥作用。在这里，我们扩展了SCAF的概念，以概括信号传导中开放式组装的基本动力学特性，比较丝状组装体和其他协同组装体（如生物分子凝聚物）的特性，并综述这一概念在细胞中的运作方式。
