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Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling

Author

Listed:
  • Julian Petersen

    (Karolinska Institutet)

  • Shane C. Wright

    (Karolinska Institutet)

  • David Rodríguez

    (Stockholm University)

  • Pierre Matricon

    (Uppsala University)

  • Noa Lahav

    (Institute of Chemistry, The Hebrew University of Jerusalem)

  • Aviv Vromen

    (Institute of Chemistry, The Hebrew University of Jerusalem)

  • Assaf Friedler

    (Institute of Chemistry, The Hebrew University of Jerusalem)

  • Johan Strömqvist

    (Single Technologies AB)

  • Stefan Wennmalm

    (Royal Institute of Technology)

  • Jens Carlsson

    (Uppsala University)

  • Gunnar Schulte

    (Karolinska Institutet
    Masaryk University)

Abstract

G protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors. They can exist and act as dimers, but the requirement of dimers for agonist-induced signal initiation and structural dynamics remains largely unknown. Frizzled 6 (FZD6) is a member of Class F GPCRs, which bind WNT proteins to initiate signaling. Here, we show that FZD6 dimerizes and that the dimer interface of FZD6 is formed by the transmembrane α-helices four and five. Most importantly, we present the agonist-induced dissociation/re-association of a GPCR dimer through the use of live cell imaging techniques. Further analysis of a dimerization-impaired FZD6 mutant indicates that dimer dissociation is an integral part of FZD6 signaling to extracellular signal-regulated kinases1/2. The discovery of agonist-dependent dynamics of dimers as an intrinsic process of receptor activation extends our understanding of Class F and other dimerizing GPCRs, offering novel targets for dimer-interfering small molecules.

Suggested Citation

  • Julian Petersen & Shane C. Wright & David Rodríguez & Pierre Matricon & Noa Lahav & Aviv Vromen & Assaf Friedler & Johan Strömqvist & Stefan Wennmalm & Jens Carlsson & Gunnar Schulte, 2017. "Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00253-9
    DOI: 10.1038/s41467-017-00253-9
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    Cited by:

    1. Yu Qian & Zhengxiong Ma & Zhenmei Xu & Yaning Duan & Yangjie Xiong & Ruixue Xia & Xinyan Zhu & Zongwei Zhang & Xinyu Tian & Han Yin & Jian Liu & Jing Song & Yang Lu & Anqi Zhang & Changyou Guo & Lihua, 2024. "Structural basis of Frizzled 4 in recognition of Dishevelled 2 unveils mechanism of WNT signaling activation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Lukas Grätz & Maria Kowalski-Jahn & Magdalena M. Scharf & Pawel Kozielewicz & Michael Jahn & Julien Bous & Nevin A. Lambert & David E. Gloriam & Gunnar Schulte, 2023. "Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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