Protein-Protein Interaction Dynamics in Cellular Signaling

Proteins rarely function in isolation within the cell; they assemble into transient or stable complexes that drive the transmission of biochemical cues. Protein–protein interaction dynamics underlie the precise regulation of signal transduction pathways, coordinating responses to environmental stimuli, developmental programmes and stress. These dynamics encompass the rates at which proteins associate and dissociate, conformational adjustments upon binding, and the modulation of binding affinities through post-translational modifications. Scaffolding proteins can orchestrate the spatial and temporal organisation of multi-protein assemblies, while allosteric effects enable distal signals to influence binding events. Dysregulation or aberrant stabilisation of specific interactions is implicated in a range of pathologies, from cancer to neurodegeneration, highlighting the importance of both understanding and modulating PPI dynamics. Recent advances in biophysical methods, such as single-molecule fluorescence and native mass spectrometry, have revealed how cooperativity and feedback loops within signalling hubs fine-tune the strength and duration of cellular responses. Small-molecule approaches that stabilise or inhibit key interfaces are opening new avenues for targeted intervention, demonstrating the translational potential of manipulating PPI landscapes.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Protein-Protein Interaction Dynamics in Cellular Signaling publication trend

The graph below shows the total number of articles in protein-protein interaction dynamics in cellular signaling across all publications each year (not limited to Nature Index journals).

Technical terms

Protein–protein interaction (PPI): physical contact between two or more proteins that enables coordination of cellular processes.

Molecular glue: small molecule that induces or stabilises a specific protein–protein complex by binding at or near the interface.

Fragment-based drug discovery (FBDD): approach that screens low-molecular-weight compounds to identify weak binders, which are elaborated into high-affinity ligands.

Cooperativity: phenomenon where the binding of one ligand or protein influences the affinity of additional binding events within a multi-component assembly.

References

1. Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein–Protein Interaction from Nonselective Fragments. Journal of the American Chemical Society (2023).
2. A Systematic Approach to the Discovery of Protein–Protein Interaction Stabilizers. ACS Central Science (2023).
3. The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein–protein interactions. Oncogene (2018).