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Cooperativity transitions driven by higher-order oligomer formations in ligand-induced receptor dimerization

Masaki Watabe, Satya N. V. Arjunan, Wei Xiang Chew, Kazunari Kaizu, and Koichi Takahashi
Phys. Rev. E 100, 062407 – Published 13 December 2019
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  • INTRODUCTION
  • THEORETICAL FRAMEWORK
  • MULTIVALENT MODELS
  • THE WG FORMULATION
  • MODEL COMPARISON
  • DIAGONALIZATION
  • CONCLUSION
  • ACKNOWLEDGMENTS
    • References

    Abstract

    While cooperativity in ligand-induced receptor dimerization has been linked with receptor-receptor couplings via minimal representations of physical observables, effects arising from higher-order oligomer, e.g., trimer and tetramer, formations of unobserved receptors have received less attention. Here we propose a dimerization model of ligand-induced receptors in multivalent form representing physical observables under basis vectors of various aggregated receptor states. Our simulations of multivalent models not only reject Wofsy-Goldstein parameter conditions for cooperativity, but show that higher-order oligomer formations can shift cooperativity from positive to negative.

    • Figure
    • Figure
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    • Received 27 May 2019

    DOI:https://doi.org/10.1103/PhysRevE.100.062407

    ©2019 American Physical Society

    Physics Subject Headings (PhySH)

    1. Physical Systems
    Biomolecules
    1. Techniques
    Collective behavior modelsNetwork Models
    Physics of Living Systems

    Authors & Affiliations

    Masaki Watabe1,*, Satya N. V. Arjunan1,2, Wei Xiang Chew1,3, Kazunari Kaizu1, and Koichi Takahashi1,4,5,†

    • 1Laboratory for Biologically Inspired Computing, RIKEN Center for Biosystems Dynamics Research, Suita, Osaka 565-0874, Japan
    • 2Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales 2052, Australia
    • 3Physics Department, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia
    • 4Institute for Advanced Biosciences, Keio University, Fujisawa, Kanagawa 252-8520, Japan
    • 5Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa 223-8522, Japan

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

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    Issue

    Vol. 100, Iss. 6 — December 2019

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    • Figure 1
      Figure 1

      Network model of observed receptor states in dimer formations. Here Φ/Φ′,M/M′, and D′ are the observed receptor-state vectors in the formation of nulls, monomers, and dimers, respectively. Each observed receptor state is represented under basis vectors of various aggregated receptor states. Here ki and di are the association and dissociation rates of the ith index, respectively; L is the ligand concentration.

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    • Figure 2
      Figure 2

      Model comparison. We compare the binding curves and Scatchard plots among the three models assuming K1=K2=100K0: the WG formulation, monovalent model (α=1), and bivalent model (α=β=1 and γ=0), for (a) and (b) kx=0.01, (c) and (d) kx=0.10, and (e) and (f) kx=0.30. The black solid and dashed lines represent the response curves for the monovalent model and the WG formulation, respectively. Black crosses represent the bivalent model.

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    • Figure 3
      Figure 3

      Cooperativity of monovalent and bivalent models. (a) Cooperativity of the monovalent model is shown as a function of the first and second ligand-receptor equilibrium constants, assuming kx=0.10. Colors represent cooperativity n of the monovalent model. The black solid and dashed lines represent no cooperativity (n=1) in the monovalent model and the WG condition given by Eq. (9), respectively. (b) and (c) Cooperativity of the bivalent model shown as a function of the eigenvalues, assuming K1=K2=100K0 and kx=0.01. Here α is varied from 0.01 to 100. (b) λ+=λ−(γ=Δ=0.00). The black and red solid lines represent cooperativity of the monovalent and bivalent models as a function of λ0, respectively. The black dashed line corresponds to no cooperativity (n=1). (c) λ+≠λ−(γ=0.10). The black line represents no cooperativity. Colors represent cooperativity n in the range from 0.7 (blue) to 1.3 (red). The black dashed line is the physical limit to satisfy the positive-definite condition.

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