Exploring IDP-Ligand Interactions: tau K18 as A Test Case.

Darius Vagrys,James Davidson,Ijen Chen,Ben Davis,Roderick E Hubbard

doi:10.3390/ijms21155257

Darius Vagrys, James Davidson + Show 3 more

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https://doi.org/10.3390/ijms21155257

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Abstract

Over the past decade intrinsically disordered proteins (IDPs) have emerged as a biologically important class of proteins, many of which are of therapeutic relevance. Here, we investigated the interactions between a model IDP system, tau K18, and nine literature compounds that have been reported as having an effect on tau in order to identify a robust IDP–ligand system for the optimization of a range of biophysical methods. We used NMR, surface plasmon resonance (SPR) and microscale thermophoresis (MST) methods to investigate the binding of these compounds to tau K18; only one showed unambiguous interaction with tau K18. Several near neighbors of this compound were synthesized and their interactions with tau K18 characterized using additional NMR methods, including 1D ligand-observed NMR, diffusion-ordered spectroscopy (DOSY) and 19F NMR. This study demonstrates that it is possible to detect and characterize IDP–ligand interactions using biophysical methods. However, care must be taken to account for possible artefacts, particularly the impact of compound solubility and where the protein has to be immobilized.

Highlights

The classical view of proteins has closely related function to a stable three-dimensional (3D) structure and the paradigm of “Sequence → Structure → Function” has dominated scientific thinking since early in the 20th century [1,2]
The importance of the biological role and function of partially or fully disordered proteins has grown in recent years, leading to an increasing interest in discovery of compounds to affect the behaviour of intrinsically disordered proteins (IDPs) in a potentially therapeutic manner
NMR Identifies Cl-NQTrp to Interact with Monomeric tau K18M

Summary

Introduction

The classical view of proteins has closely related function to a stable three-dimensional (3D) structure and the paradigm of “Sequence → Structure → Function” has dominated scientific thinking since early in the 20th century [1,2]. By the time the first experimentally derived 3D models of protein structure were available, this “Structure → Function” relationship was widely accepted and underpins our understanding and appreciation of most protein structures [3,4]. It was in 1975 that the first ideas of peptides and proteins (glucagon), having a biological function without having a defined structure, emerged [5]. The identification and characterization of IDP–ligand interactions has been challenging [8,9,10]

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