Regulation of Protein-Protein Binding through the Coupling Between Phosphorylation and Intrinsic Disorder

Abstract

Phosphorylation offers a dynamic way to regulate protein activity, subcellular localization, and stability. At the same time phosphorylation sites are often located in the intrinsically disordered regions. We studied the effect of phosphorylation on protein binding for different types of complexes from human proteome. We estimated the effect of phosphorylation on complex stability and found that the majority of complexes do not show significant stability differences upon phosphorylation or de-phosphorylation. However, we also found that phosphorylation sites tend to be located on binding interfaces, may orthosterically modulate the strength of interactions and for about one-third of all complexes cause relatively large changes in binding energy. All this suggests that processes of phosphorylation, binding and disorder-to-order transitions might be tightly coupled with each other. Indeed we showed that there is significant association between phosphorylation, disorder and binding for serine and threonine residues in human. However, tyrosine phosphorylation might not be necessarily associated with binding through disorder-to-order transitions and is often observed in ordered regions which are not disordered in unbound state. We suggest possible mechanisms of how phosphorylation might regulate protein-protein binding via intrinsic disorder, for example, phosphorylation in disordered regions may prevent disorder-to-order transition and subsequent protein-protein binding.