Signalling by co-operative higher-order assembly formation: linking evidence at molecular and cellular levels
Boštjan Kobe, Jeffrey D. Nanson, Mikayla Hoad, Antje Blumenthal, Yann Gambin, Emma Sierecki, Katryn J. Stacey, Thomas Ve, Randal Halfmann
Abstract
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.