Spatial and temporal organization of multi-protein assemblies: achieving sensitive control in information-rich cell-regulatory systems

Abstract

The regulation of cellular processes in living organisms requires signalling systems that have a high signal-to-noise ratio. This is usually achieved by transient, multi-protein complexes that assemble cooperatively. Even in the crowded environment of the cell, such assemblies are unlikely to form by chance, thereby providing a sensitive regulation of cellular processes. Furthermore, selectivity and sensitivity may be achieved by the requirement for concerted folding and binding of previously unfolded components. We illustrate these features by focusing on two essential signalling pathways of eukaryotic cells: first, the monitoring and repair of DNA damage by non-homologous end joining, and second, the mitotic spindle assembly checkpoint, which detects and corrects defective attachments of chromosomes to the kinetochore. We show that multi-protein assemblies moderate the full range of functional complexity and diversity in the two signalling systems. Deciphering the nature of the interactions is central to understanding the mechanisms that control the flow of information in cell signalling and regulation.

Structural and mechanistic insight into Holliday-junction dissolution by Topoisomerase IIIα and RMI1

“…This work serves as an example of how binding proteins, such as RMI1, modulate topoisomerase function within their large assembles (also referred as toposomes 49 ). Epitopes such as the RMI1 loop, which are unstructured in isolation, can nonetheless assume crucial catalytic and regulatory roles when put in the context of these macromolecular machines 50 .…”

The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation

“…Because multiprotein complexes that form cooperatively would less likely to be formed fortuitously (Blundell et al, 2002; Bolanos-Garcia et al, 2012), the cooperative association of higher order SAC signaling complexes resulting from binary interactions that are both specific and of low-affinity should favor the amplification of specific signals to mount an effective SAC response. The cooperative assembly of the KMN subcomplexes Mis12 and Ndc80 illustrates how the establishment of higher order signaling complexes can regulate the SAC.…”

Dynamic multiprotein assemblies shape the spatial structure of cell signaling

“…This leads to questions such as how molecules efficiently find their proper location in cell space (Nussinov, 2012). In contrast, here we view cellular signaling as transient pre-organized and inter-connected protein assemblies which span the cell, with signaling taking place via dynamic conformational population shifts (Bolanos-Garcia et al, 2012; Nussinov, 2013). Such a multivalent, typically membrane-anchored network, with interactions forming and breaking endows cell signaling with gel-like properties (Figure 1).…”

“…A living cell is an organized pattern, structured in space and time (Bolanos-Garcia et al, 2012; Harold, 2005; Nussinov, 2013). Architecture is what ultimately distinguishes a living cell from some haphazard assemblage in solution (McLaughlin et al, 2012).…”