Anchor Residues Govern Binding and Folding of an Intrinsically Disordered Domain

Minimal protein mimics have yielded novel classes of protein- protein interaction inhibitors; however, this success has not been extended to targeting intrinsically disordered proteins, which represent a significant proportion of important therapeutic targets. We sought to determine the requirements for binding an intrinsically disordered region (IDR) by its native binding partner as a prelude to developing minimal protein mimics that regulate IDR interactions. Our analysis reinforces the hypothesis that IDRs reside on a fulcrum between unfolded and folded states and that a handful of key binding residues on partner protein surfaces dictate their folding. Our studies also suggest that minimal mimics of protein surfaces may not offer specific ligands for IDRs and that it would be more judicious to target the globular protein partners of IDRs.

Automated summary

This study aims to determine the requirements for binding an intrinsically disordered region (IDR) by its native binding partner, in order to develop minimal protein mimics that can regulate IDR interactions. The findings suggest that key binding residues on partner protein surfaces play a crucial role in determining their folding, and targeting the globular protein partners of IDRs may be more effective.