Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins

Elin Karlsson,Cristina Paissoni,Amanda M Erkelens,Zeinab A Tehranizadeh,Frieda A Sorgenfrei,Eva Andersson,Weihua Ye,Carlo Camilloni,Per Jemth

doi:10.1074/jbc.ra120.015645

Abstract

Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway.

Highlights

Disordered protein domains often have multiple binding partners
Intrinsically disordered proteins (IDPs) often participate in regulatory functions in the cell by engaging in complex interaction networks that fine-tune cellular responses to environmental cues [40]
One feature common to many IDPs, and which has likely contributed to their abundance in regulatory functions, is the ability to interact with several partners that are competing for binding [41]

Summary

Introduction

Disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. The functional advantages of disordered proteins include exposure of linear motifs for association with other proteins, accessibility for post-translational modifications, formation of large binding interfaces, and the ability to interact with multiple partners. These properties make IDPs suitable for regulatory functions in the cell, for example as hubs in interaction networks governing signal transduction pathways and transcriptional regulation [2].

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Results

Conclusion