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Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations

Author

Listed:
  • Lukas Grätz

    (Sec. Receptor Biology & Signaling)

  • Maria Kowalski-Jahn

    (Sec. Receptor Biology & Signaling)

  • Magdalena M. Scharf

    (Sec. Receptor Biology & Signaling)

  • Pawel Kozielewicz

    (Sec. Receptor Biology & Signaling)

  • Michael Jahn

    (Biotechnology and Health, Science for Life Laboratory, KTH – Royal Institute of Technology
    Bioinformatics platform)

  • Julien Bous

    (Sec. Receptor Biology & Signaling)

  • Nevin A. Lambert

    (Augusta University)

  • David E. Gloriam

    (University of Copenhagen)

  • Gunnar Schulte

    (Sec. Receptor Biology & Signaling)

Abstract

The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD1-10) paralogs and Smoothened, remains one of the most enigmatic GPCR families. This class mediates signaling predominantly through Disheveled (DVL) or heterotrimeric G proteins. However, the mechanisms underlying pathway selection are elusive. Here we employ a structure-driven mutagenesis approach in combination with an extensive panel of functional signaling readouts to investigate the importance of conserved state-stabilizing residues in FZD5 for signal specification. Similar data were obtained for FZD4 and FZD10 suggesting that our findings can be extrapolated to other members of the FZD family. Comparative molecular dynamics simulations of wild type and selected FZD5 mutants further support the concept that distinct conformational changes in FZDs specify the signal outcome. In conclusion, we find that FZD5 and FZDs in general prefer coupling to DVL rather than heterotrimeric G proteins and that distinct active state micro-switches in the receptor are essential for pathway selection arguing for conformational changes in the receptor protein defining transducer selectivity.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40213-0
    DOI: 10.1038/s41467-023-40213-0
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    References listed on IDEAS

    as
    1. Shane C. Wright & Paweł Kozielewicz & Maria Kowalski-Jahn & Julian Petersen & Carl-Fredrik Bowin & Greg Slodkowicz & Maria Marti-Solano & David Rodríguez & Belma Hot & Najeah Okashah & Katerina Strako, 2019. "A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    2. Paweł Kozielewicz & Ainoleena Turku & Carl-Fredrik Bowin & Julian Petersen & Jana Valnohova & Maria Consuelo Alonso Cañizal & Yuki Ono & Asuka Inoue & Carsten Hoffmann & Gunnar Schulte, 2020. "Structural insight into small molecule action on Frizzleds," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    3. Diane C. Slusarski & Victor G. Corces & Randall T. Moon, 1997. "Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling," Nature, Nature, vol. 390(6658), pages 410-413, November.
    4. 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.
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