Signaling activations through G-protein-coupled-receptor aggregations

Masaki Watabe, Hideaki Yoshimura, Satya N. V. Arjunan, Kazunari Kaizu, and Koichi Takahashi

Phys. Rev. E 102, 032413 – Published 22 September 2020

Abstract

Eukaryotic cells transmit extracellular signal information to cellular interiors through the formation of a ternary complex made up of a ligand (or agonist), G-protein, and G-protein-coupled receptor (GPCR). Previously formalized theories of ternary complex formation have mainly assumed that observable states of receptors can only take the form of monomers. Here, we propose a multiary complex model of GPCR signaling activations via the vector representation of various unobserved aggregated receptor states. Our results from model simulations imply that receptor aggregation processes can govern cooperative effects in a regime inaccessible by previous theories. In particular, we show how the affinity of ligand-receptor binding can be largely varied by various oligomer formations in the low concentration range of G-protein stimulus.

Received 16 April 2020
Revised 3 August 2020
Accepted 31 August 2020

DOI:https://doi.org/10.1103/PhysRevE.102.032413

Physics Subject Headings (PhySH)

Biomolecular interactions Protein-ligand interactions

Signaling networks

Physics of Living Systems

Authors & Affiliations

Masaki Watabe^1,*, Hideaki Yoshimura ², Satya N. V. Arjunan ^1,3, Kazunari Kaizu¹, and Koichi Takahashi^1,4,†

¹Laboratory for Biologically Inspired Computing, RIKEN Center for Biosystems Dynamics Research, Suita, Osaka 565-0874, Japan
²School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
³Lowy Cancer Research Centre, The University of New South Wales, Sydney 2052, Australia
⁴Institute for Advanced Biosciences, Keio University, Fujisawa, Kanagawa 252-8520, Japan

^*Corresponding author: masaki@riken.jp
^†Corresponding author: ktakahashi@riken.jp

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Vol. 102, Iss. 3 — September 2020

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Images

Figure 1
Schematic illustration of the simplest ternary complex model [1, 2]. A ligand (red bullet) and G-protein (orange object) can bind to a monomeric GPCR (green Y-shaped object) with equilibrium constants $K_{ℓ 0}$ and $K_{g 0}$ , respectively. A ternary complex composed of a ligand, G-protein, and receptor can be formed in two ways: ( $i$ ) ligands can interact with the receptors binding to G-proteins with equilibrium constant $α K_{ℓ 0}$ , and ( $ii$ ) G-proteins can bind to the ligand-bound receptors with equilibrium constant $α K_{g 0}$ , where $α$ is a cooperativity factor that denotes the mutual effect of the receptor-binding affinity to the ligand and G-protein.
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Figure 2
Multiary complex formation via ligand-bound-receptor dimerization in GPCR signaling activations. (a) Schematic illustration of the ternary complex formation (black arrows) and receptor aggregation processes (blue arrows) [3]. The multiary complex is composed of a ligand (red bullet), G-protein (orange object), and various aggregated receptors (green Y-shaped objects). (b) Network diagrams of the multiary complex model. (b1) Multivalent form of the simplest ternary complex model. (b2) Dimer formations of ligand-bound receptors. (b3) First-order interactions of ligand and G-protein to receptor states. (b4) Second-order interactions of receptor states to G-protein-bound-receptor states. $L$ (blue) and $G$ (red) represent the input concentrations of ligand and G-protein stimuli, respectively. See the main text for detailed descriptions of state vectors and model parameters.
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Figure 3
Model comparison between the simplest ternary complex model (top row) and the monovalent cell model (bottom row). $L$ and $G$ represent the input concentrations of ligand and G-protein stimuli, respectively. (a) Ligand-receptor binding curve as a function of ligand stimulus $L$ , is given by Eq. (11), where $G / K_{g 0} = 0.1, α = 0.08$ (blue), 0.5 (light-blue), 1.0 (black dots), 3.0 (light-violet), and 30 (violet). (b) Overall affinity of ligand-receptor binding ( $K^{'} / K_{ℓ 0}$ ) as a function of G-protein stimulus is given by the Eq. (12), for $G / K_{g 0} = 0.1$ and $α = 0.08$ , 0.5, 1.0, 3.0, 30. (c) Colors represent the binding affinity of the ternary complex model in the range from 0 (blue) to $\sim 1$ (green) and $\geq 2$ (red); the black dashed line shows $K^{'} / K_{ℓ 0} = 1$ . (d) For $α = 1$ and $k_{x} = 0$ (black dots), $10^{- 4}$ (light-orange), $10^{- 3}$ (orange), and $10^{- 2}$ (dark-orange), ligand-receptor binding curves are shown as a function of ligand stimulus $L / K_{ℓ 0}$ . (e) For $α = 1$ and $k_{x} = 0, 10^{- 4}, 10^{- 3}$ , and $10^{- 2}$ , overall affinities of ligand-receptor binding are shown as a function of G-protein stimulus $G / K_{g 0}$ . (f) Color represents the binding affinity of the monovalent cell model as a function of $α$ and $G / K_{g 0}$ , assuming $k_{x} = 0.001$ ; the black dashed and solid lines represent $K^{'} / K_{ℓ 0} = 1$ in the simplest ternary complex model and the monovalent cell model, respectively.
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Figure 4
Transition of the overall affinity in the multivalent cell models is shown as a function of the lumped parameter $k_{x}$ , assuming $α = 1$ and $G / K_{g 0} = 10^{- 3}$ . Each colored line represents the monovalent (red), bivalent (blue), trivalent (green), tetravalent (pink), and pentavalent (violet) models; the dashed black line denotes $K^{'} / K_{ℓ 0} = 1$ .
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