On the specificity of protein-protein interactions in the context of disorder

With the increased focus on intrinsically disordered proteins (IDPs) and their large interac-tomes, the question about their specificity - or more so on their multispecificity - arise. Here we recapitulate how specificity and multispecificity are quantified and address through examples if IDPs in this respect differ from globular proteins. The conclusion is that quantitatively, globular proteins and IDPs are similar when it comes to specificity. However, compared with globular proteins, IDPs have larger interactome sizes, a phe-nomenon that is further enabled by their flexibility, repetitive binding motifs and propen-sity to adapt to different binding partners. For IDPs, this adaptability, interactome size and a higher degree of multivalency opens for new interaction mechanisms such as facili-tated exchange through trimer formation and ultra-sensitivity via threshold effects and ensemble redistribution. IDPs and their interactions, thus, do not compromise the defin-ition of specificity. Instead, it is the sheer size of their interactomes that complicates its calculation. More importantly, it is this size that challenges how we conceptually envision, interpret and speak about their specificity.

Automated summary

Intrinsically disordered proteins (IDPs) share similar specificity with globular proteins quantitatively, but have larger interactome sizes, adaptability, and a higher degree of multivalency. This allows for new interaction mechanisms and challenges traditional concepts of specificity.