Role of Ordered Proteins in the Folding-Upon-Binding of Intrinsically Disordered Proteins

Abstract

In this work, we quantitatively investigate the thermodynamic analogy between the folding of monomeric proteins and the interactions of intrinsically disordered proteins (IDPs). Motivated by the hypothesis that similar hydrophobic forces guide both globular protein folding and also IDP interactions, we present a unified experimental and computational investigation of the coupling between the folding and binding of the intrinsically disordered tail of FCP1 when interacting with the cooperatively folding winged-helix domain of Rap74. Our calorimetric measurements quantitatively demonstrate the significance of hydrophobic interactions for this binding event. Our computational studies indicate that IDPs relieve frustration at the surface of ordered proteins to generate a minimally frustrated complex that is strikingly similar to a globular monomeric protein. In summary, these results not only quantify the thermodynamic forces driving disordered protein interactions but also highlight the role of ordered proteins for IDP function.

Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins

“…However, there is an offset in the values of Δ H for the Ordovician-Silurian and human complexes as compared to the Cambrian-like complex at pH 6.5 such that the enthalpic contribution, which mirrors bond strength, is weakened in the higher-affinity complexes. Instead, the thermodynamic basis for the higher affinity is a less unfavorable or even favorable entropic contribution to the overall affinity, a result that is qualitatively very similar to another IDP interaction—that between FCP1 and Rap74 ( 19 ). At pH 7.5, this offset is smaller, and all three complexes display a similar contribution from Δ H .…”

Concatenation of 14-3-3 with partner phosphoproteins as a tool to study their interaction

“…Phosphorylation serves as a selective filter, promoting client binding to 14-3-3 when client is phosphorylated, and preventing binding when the same client is not phosphorylated. Phosphopeptide binding in the AGs of 14-3-3 preferentially occurs when the phosphoresidue embedded consensus motifs reside within intrinsically disordered regions (IDRs) of protein partners 17 that contain sufficient flexibility required for binding to a rather rigid 14-3-3 dimer 18–22 . Motif I (R[S/F/Y/W]XpSXP), motif II (RX[S/Y/F/W/T/Q/A/D]Xp(S/T)X[P/L/M]) and motif III (pSX 1–2 –COOH), where pS/T is phosphorylated serine or threonine, have been characterised 23,24 , although targets deviating from these canonical motifs have also been reported 25,26 .…”

Alanine and proline content modulate global sensitivity to discrete perturbations in disordered proteins

“…21 A key feature of these models is the induced folding of disordered structure from binding that result in the thermodynamic coupling of distant protein regions. Binding-induced folding has been observed for many IDPs 16,[20][21][22][23][24][25] and characterized in detail, in terms of structures, 23 binding kinetics, 24 and interaction energies. 25 Global organization of IDP structure in the absence of binding or folding has also been reported.…”

“…Binding-induced folding has been observed for many IDPs 16,[20][21][22][23][24][25] and characterized in detail, in terms of structures, 23 binding kinetics, 24 and interaction energies. 25 Global organization of IDP structure in the absence of binding or folding has also been reported. 26,27 The physicochemical mechanisms that organize disordered protein structures on a global scale without cooperative folding are not yet fully understood.…”