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

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.

Conformational Dynamics of the Soluble and Membrane-Bound Forms of Interleukin-1 Receptor Type-1: Insights into Linker Flexibility and Domain Orientation

“…Altogether, our simulations expand the current understanding of the dynamic features of the soluble and membrane-bound forms of IL-1R1, corroborating and mounting on the observations of other studies [ 13 , 14 , 15 ]. The incorporation of dynamic features, such as the ones highlighted in the present work, provide a better understanding of the differences between the soluble and membrane-bound IL-1R1-ECD conformational landscape.…”

Composite immune marker scores associated with severe mental disorders and illness course

“…While the mechanism of IL-18 and IL-18BP are well established, the regulation and function of soluble IL-18R1 and IL-18RAP are less established. Membrane bound IL-18R1 and IL-18R2 promotes IL-18 signaling and is further amplified by IL-18RAP ( Yang, 2020 ). Conversely, their soluble forms act as decoy receptors and inhibit IL-18 signaling ( Reznikov et al, 2002 ).…”

Co-Isolation of Cytokines and Exosomes: Implications for Immunomodulation Studies

“…To decrease a cytokines' effective range and thereby maintain specificity, many cytokines also function as a membrane-bound protein. Several cytokines and their receptors including IL-1, M-CSF, TGFb, and TNFa have been reported in other studies to exist in both soluble and membrane-bound forms, both which are biologically active (19)(20)(21)(22)(23). Most notably, proinflammatory cytokine TNFa was found to also exist in a transmembrane form where it functions as a precursor to soluble TNFa and is able to exert its own cytotoxic activity by acting as a ligand for TNF receptor 2 (TNF-R2) (21,24).…”