Abstract
Achieving facile specific recognition is essential for intrinsically disordered proteins (IDPs) that are involved in cellular signaling and regulation. Consideration of the physical time scales of protein folding and diffusion-limited protein-protein encounter has suggested that the frequent requirement of protein folding for specific IDP recognition could lead to kinetic bottlenecks. How IDPs overcome such potential kinetic bottlenecks to viably function in signaling and regulation in general is poorly understood. Our recent computational and experimental study of cell-cycle regulator p27 (Ganguly et al., J. Mol. Biol. (2012)) demonstrated that long-range electrostatic forces exerted on enriched charges of IDPs could accelerate protein-protein encounter via “electrostatic steering” and at the same time promote “folding-competent” encounter topologies to enhance the efficiency of IDP folding upon encounter. Here, we further investigated the coupled binding and folding mechanisms and the roles of electrostatic forces in the formation of three IDP complexes with more complex folded topologies. The surface electrostatic potentials of these complexes lack prominent features like those observed for the p27/Cdk2/cyclin A complex to directly suggest the ability of electrostatic forces to facilitate folding upon encounter. Nonetheless, similar electrostatically accelerated encounter and folding mechanisms were consistently predicted for all three complexes using topology-based coarse-grained simulations. Together with our previous analysis of charge distributions in known IDP complexes, our results support a prevalent role of electrostatic interactions in promoting efficient coupled binding and folding for facile specific recognition. These results also suggest that there is likely a co-evolution of IDP folded topology, charge characteristics, and coupled binding and folding mechanisms, driven at least partially by the need to achieve fast association kinetics for cellular signaling and regulation.
Highlights
Cellular signaling and regulation are frequently mediated by proteins that, in part or as a whole, lack stable structures under physiological conditions [1,2,3]
While fulfilling important functional constraints such as structural plasticity for binding numerous specific targets, protein intrinsic disorder can lead to potential kinetic bottlenecks to be viable in cellular signaling and regulation
Our previous work on the p27/Cdk2/cyclin A complex has revealed a mechanism where nonspecific electrostatic interactions enhance the proteinprotein encounter kinetics and promote folding-competent encounter topologies to increase the efficiency of intrinsically disordered proteins (IDPs) folding upon encounter [24]
Summary
Cellular signaling and regulation are frequently mediated by proteins that, in part or as a whole, lack stable structures under physiological conditions [1,2,3]. Such intrinsically disordered proteins (IDPs) are highly prevalent in proteomes [4] and overrepresented in diseases pathways [5,6]. Understanding the physical basis of how intrinsic disorder mediates protein function (and how such functional mechanism may fail in human diseases [15]) is of fundamental significance and has attracted intense interests in recent years [16]. Important progresses have been made on characterizing the conformational properties of unbound IDPs and determining how these conformational properties contribute to efficient and reliable interactions [16,17,18,19,20,21,22]
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