Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Abstract

The sequence-structure-function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well-defined three-dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

Keywords: binding kinetics; fuzzy interaction; intrinsically disordered proteins; molecular recognition; transition state.

Figure 1

Examples of intrinsically disordered protein (IDP) complex with various combinations of molecular recognition features (MoRFs). IDPs are shown in rainbow color and the targets are shown in gray. PDB IDs are: Bim/MCL‐1 (2NL9), CSL/notch (2FO1), FOXO3a/KIX (2LQI), MLV IN/Brd4 (2N3K), Rb/E2F1‐DP1 (2AZE), and ExsC/ExsE (3KXY)

Figure 2

Binding of E3 to Im3. (a) Crystal structure of E3/Im3 complex. E3 is shown in rainbow color and Im3 in gray. (b) Disorder propensity prediction of E3 using three different predictors: IUPred2 (black), MFDp2 (red), and PONDR VL‐XT (blue). (c) Location of E3 on the charge‐hydrophobicity plot. The black line indicates the boundary between the intrinsically disordered proteins (IDPs) region and the ordered proteins. (d) Effect of salt concentration on k _on for E3^WT and E3^IDP 98

Figure 3

Illustrations of intrinsically disordered protein (IDP) encoded binding and target templated binding. (a) ϕ‐values for the disordered BH3‐only protein PUMA binding with BCL‐2–like proteins A1 and MCL‐1.141 (b) correlation of α‐value from linear free‐energy relationships (LFER) analysis for c‐Myb with the hydrophobic solvent accessible surface area in the binding site on KIX138