Intrinsically disordered proteins: modes of binding with emphasis on disordered domains

Abstract

Our notions of protein function have long been determined by the protein structure–function paradigm. However, the idea that protein function is dictated by a prerequisite complementarity of shapes at the binding interface is becoming increasingly challenged. Interactions involving intrinsically disordered proteins (IDPs) have indicated a significant degree of disorder present in the bound state, ranging from static disorder to complete disorder, termed ‘random fuzziness’. This review assesses the anatomy of an IDP and relates how its intrinsic properties permit promiscuity and allow for the various modes of interaction. Furthermore, a mechanistic overview of the types of disordered domains is detailed, while also relating to a recent example and the kinetic and thermodynamic principles governing its formation.

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

“…IDRs lack the large hydrophobic amino acids that form structured domains, and can, therefore, conduct rapid exchanges between multiple conformations to assemble condensates without altering the affinity of binding interactions during LLPS [ 200 , 201 ]. Increased cell complexity in eukaryotes is correlated with a significantly higher level of disorder compared to prokaryotes [ 202 ], implying the lack of an ordered, three-dimensional structure confers higher flexibility in protein–protein interactions that are instrumental in cell signaling and molecular communication [ 203 , 204 , 205 ]. Viruses employ several successful tactics to hijack and control host biomolecular condensates by utilizing the unique features of IDRs in their proteins to accomplish this task [ 206 ].…”

Digging into the 3D Structure Predictions of AlphaFold2 with Low Confidence: Disorder and Beyond

“…The first question is whether it is possible to reveal conditional order within these intrinsically disordered regions (IDRs), from amino acid sequence information alone. Such IDRs may be involved in molecular recognition, to which hydrophobic interactions make major contributions [ 13 , 14 ]. In many cases, these regions undergo a disorder-to-order transition (induced folding) to a more structured state upon binding with a partner [ 15 ].…”

Intrinsic protein disorder uncouples affinity from binding specificity

“…A few of the best‐studied examples are binding of eIF4G to eIF4E, 6 p53 to MDM2, 7 E‐cadherin to β‐catenin, 8,9 p27 to the complex of Cyclin A/Cdk 2, 10 CREB to CBP KIX domain, 11 and inhibitor‐2 to PP1 12,13 . Structural analysis of these and other examples has ascertained that the binding mode of IDPs/IDRs differs from that of globular proteins 14 . IDPs do not have flat interfaces, rather, they fit in an extended conformation into the hydrophobic binding cleft of their partners, either via a short recognition motif 15 or via a longer disordered domain 16 .…”

“… 12 , 13 Structural analysis of these and other examples has ascertained that the binding mode of IDPs/IDRs differs from that of globular proteins. 14 IDPs do not have flat interfaces, rather, they fit in an extended conformation into the hydrophobic binding cleft of their partners, either via a short recognition motif 15 or via a longer disordered domain. 16 In both binding modes, the interface region is a larger part of the protein, and is better packed, in the case of IDPs.…”