Comparative Analyses of the Conformational Dynamics Between the Soluble and Membrane-Bound Cytokine Receptors

Chao-Yie Yang

doi:10.1038/s41598-020-64034-z

Abstract

Cytokine receptors receive extracellular cues by binding with cytokines to transduce a signaling cascade leading to gene transcription in cells. Their soluble isoforms, functioning as decoy receptors, contain only the ectodomain. Whether the ectodomains of cytokine receptors at the membrane exhibit different conformational dynamics from their soluble forms is unknown. Using Stimulation-2 (ST2) as an example, we performed microsecond molecular dynamics (MD) simulations to study the conformational dynamics of the soluble and the membrane-bound ST2 (sST2 and ST2). Combined use of accelerated and conventional MD simulations enabled extensive sampling of the conformational space of sST2 for comparison with ST2. Using the interdomain loop conformation as the reaction coordinate, we built a Markov State Model to determine the slowest implied timescale of the conformational transition in sST2 and ST2. We found that the ectodomain of ST2 undergoes slower conformational relaxation but exhibits a faster rate of conformational transition in a more restricted conformational space than sST2. Analyses of the relaxed conformations of ST2 further suggest important contributions of interdomain salt-bridge interactions to the stabilization of different ST2 conformations. Our study elucidates differential conformational properties between sST2 and ST2 that may be exploited for devising strategies to selectively target each isoform.

Highlights

The interleukin-1 (IL-1) family of cytokines and their receptors are key regulators of innate immunity that can initiate inflammatory response in hosts to fend off foreign antigens[1,2]
In patients developing graft versus host disease (GVHD) after hematopoietic cells transplantation (HCT), excessive increases of the sST2 level reduce the pool of IL-3318 for activation of the ST2/IL-33 axis in Th2, ILC2, and Tregs cells that leads to unrestrained inflammation in early GVHD progression[19,20,21]
After the projections of ST2 conformations to PC1-PC3, we found that conformations of sST2 were mapped to a circular path along PC1 and PC2 (Fig. 2A) suggesting a nonlinear coupled motion of large amplitude domain motions (PC1) and collective backbone vibration (PC2) dominated the conformational transition

Summary

Introduction

The interleukin-1 (IL-1) family of cytokines and their receptors are key regulators of innate immunity that can initiate inflammatory response in hosts to fend off foreign antigens[1,2]. Because aMD was not implemented to sample ST2, we performed cMD simulations using three different orientations of ST2ECD on the membrane (Fig. 1) to map the conformational space of ST2ECD (or ST2 hereafter). We first aligned the D1D2 domain of ST2 conformations to the crystal structure of ST2ECD in complex with IL-33 to determine the backbone motions of each domain for the initial 108 ns of sST2, ST21-3 using the cMD simulations.

Results

Conclusion