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Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers

Author

Listed:
  • Maxime Zoenen

    (IRIBHM, Université Libre de Bruxelles, Campus Erasme)

  • Eneko Urizar

    (IRIBHM, Université Libre de Bruxelles, Campus Erasme)

  • Stéphane Swillens

    (IRIBHM, Université Libre de Bruxelles, Campus Erasme)

  • Gilbert Vassart

    (IRIBHM, Université Libre de Bruxelles, Campus Erasme)

  • Sabine Costagliola

    (IRIBHM, Université Libre de Bruxelles, Campus Erasme)

Abstract

Glycoprotein hormone receptors show strong negative cooperativity. As a consequence, at physiological hormone concentrations, a single agonist binds to a receptor dimer. Here we present evidence that constitutively active receptors lose cooperative allosteric regulation in direct relation with their basal activity. The most constitutive mutants lost nearly all cooperativity and showed an increase of initial tracer binding, reflecting the ability of each protomer to bind with equal affinity. Allosteric interaction between the protomers takes place at the transmembrane domain. The allosteric message resulting from hormone binding to the ectodomain of one protomer travels 'downward' to its transmembrane domain, before affecting the transmembrane domain of the other protomer. This results in transmission of an 'upward' message lowering the binding affinity of the ectodomain of the second protomer. Our results demonstrate a direct relation between the conformational changes associated with activation of the transmembrane domain and the allosteric behaviour of glycoprotein hormone receptors dimers.

Suggested Citation

  • Maxime Zoenen & Eneko Urizar & Stéphane Swillens & Gilbert Vassart & Sabine Costagliola, 2012. "Evidence for activity-regulated hormone-binding cooperativity across glycoprotein hormone receptor homomers," Nature Communications, Nature, vol. 3(1), pages 1-9, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1991
    DOI: 10.1038/ncomms1991
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