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.Frizzled 6 (FZD6) is a G protein-coupled receptor (GPCR) involved in several cellular processes. Here, the authors use live cell imaging and spectroscopy to show that FZD6 forms dimers, whose association is regulated by WNT proteins and that dimer dissociation is crucial for FZD6 signaling.

Department of Applied Physics Experimental Biomolecular Physics group Science for Life Laboratory Royal Institute of Technology Solna SE 171 65 Sweden

Department of Physiology and Pharmacology Section for Receptor Biology and Signaling Karolinska Institutet SE 171 77 Stockholm Sweden

Department of Physiology and Pharmacology Section for Receptor Biology and Signaling Karolinska Institutet SE 171 77 Stockholm Sweden Department of Experimental Biology Faculty of Science Masaryk University Kotlarska 2 61137 Brno Czech Republic

Institute of Chemistry The Hebrew University of Jerusalem Givat Ram Jerusalem 91904 Israel

Science for Life Laboratory Department of Biochemistry and Biophysics Stockholm University SE 106 91 Stockholm Sweden

Science for Life Laboratory Department of Cell and Molecular Biology Uppsala University BMC Box 596 SE 751 24 Uppsala Sweden

Single Technologies AB SE 114 28 Stockholm Sweden

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$a Petersen, Julian $u Department of Physiology & Pharmacology, Section for Receptor Biology & Signaling, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

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$a Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling / $c J. Petersen, SC. Wright, D. Rodríguez, P. Matricon, N. Lahav, A. Vromen, A. Friedler, J. Strömqvist, S. Wennmalm, J. Carlsson, G. Schulte,

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$a 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.Frizzled 6 (FZD6) is a G protein-coupled receptor (GPCR) involved in several cellular processes. Here, the authors use live cell imaging and spectroscopy to show that FZD6 forms dimers, whose association is regulated by WNT proteins and that dimer dissociation is crucial for FZD6 signaling.

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$a Wright, Shane C $u Department of Physiology & Pharmacology, Section for Receptor Biology & Signaling, Karolinska Institutet, SE-171 77, Stockholm, Sweden.

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$a Rodríguez, David $u Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, SE-106 91, Stockholm, Sweden.

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$a Matricon, Pierre $u Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, SE-751 24, Uppsala, Sweden.

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$a Lahav, Noa $u Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, 91904, Israel.

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$a Vromen, Aviv $u Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, 91904, Israel.

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$a Friedler, Assaf $u Institute of Chemistry, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, 91904, Israel.

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$a Strömqvist, Johan $u Single Technologies AB, SE-114 28, Stockholm, Sweden.

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$a Wennmalm, Stefan $u Department of Applied Physics, Experimental Biomolecular Physics group, Science for Life Laboratory, Royal Institute of Technology, Solna, SE-171 65, Sweden.

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$a Carlsson, Jens $u Science for Life Laboratory, Department of Cell and Molecular Biology, Uppsala University, BMC, Box 596, SE-751 24, Uppsala, Sweden.

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$a Schulte, Gunnar $u Department of Physiology & Pharmacology, Section for Receptor Biology & Signaling, Karolinska Institutet, SE-171 77, Stockholm, Sweden. gunnar.schulte@ki.se. Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlarska 2, 61137, Brno, Czech Republic. gunnar.schulte@ki.se.

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