Binding Mechanisms of Intrinsically Disordered Proteins: Theory, Simulation, and Experiment

Abstract

In recent years, protein science has been revolutionized by the discovery of intrinsically disordered proteins (IDPs). In contrast to the classical paradigm that a given protein sequence corresponds to a defined structure and an associated function, we now know that proteins can be functional in the absence of a stable three-dimensional structure. In many cases, disordered proteins or protein regions become structured, at least locally, upon interacting with their physiological partners. Many, sometimes conflicting, hypotheses have been put forward regarding the interaction mechanisms of IDPs and the potential advantages of disorder for protein-protein interactions. Whether disorder may increase, as proposed, e.g., in the “fly-casting” hypothesis, or decrease binding rates, increase or decrease binding specificity, or what role pre-formed structure might play in interactions involving IDPs (conformational selection vs. induced fit), are subjects of intense debate. Experimentally, these questions remain difficult to address. Here, we review experimental studies of binding mechanisms of IDPs using NMR spectroscopy and transient kinetic techniques, as well as the underlying theoretical concepts and numerical methods that can be applied to describe these interactions at the atomic level. The available literature suggests that the kinetic and thermodynamic parameters characterizing interactions involving IDPs can vary widely and that there may be no single common mechanism that can explain the different binding modes observed experimentally. Rather, disordered proteins appear to make combined use of features such as pre-formed structure and flexibility, depending on the individual system and the functional context.

Tri-arginine exosite patch of caspase-6 recruits substrates for hydrolysis

“…Caspase-6 also contains a stretch of amino acids 24 AFYKREMF 31 , which is unresolved in all caspase-6 structures, and which we previously identified as being intrinsically disordered and thus likely to participate in protein-protein interactions (55). Intrinsically disordered domains often bind partners with high specificity but low affinity due to the transient and reversible nature of their folding (71)(72)(73). These characteristics are consistent with the binding and release properties required by the caspase family for rapid substrate processing.…”

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

“…Conformational selection and induced fit have been widely applied to explain the coupled folding-binding process of IDPs/IDRs. 75,112,113 Which mechanism dominates during the binding process depends on several factors, including the structure preference and conformational dynamics of the IDPs/IDRs, the association rate, and the concentration as well. [114][115][116][117][118][119][120][121][122][123][124][125] It has been established that IDPs/IDRs sample a variety of conformations rapidly.…”

Dual roles of electrostatic-steering and conformational dynamics in the binding of calcineurin’s intrinsically-disordered recognition domain to calmodulin

“…In contrast, other examples such as p53 up-regulated modulator of apoptosis (PUMA) do not adhere to this paradigm, as its rapid association rate depends on temperature and solvent viscosity in manners atypical of diffusion-limited association events (33)(34)(35) . For PUMA, it was speculated that association is driven by an induced-fit mechanism that depends on tight interactions between binding partners (34), in contrast to the encounter complex suggested by Shammas et al Hence, there is likely a system-dependent (36) interplay between properties of the IDP conformational ensemble, conformational dynamics and their diffusion-mediated encounters with binding partners that dictate observed PPI association rates.…”