IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40213-0.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40213-0
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-40213-0?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. 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.
    3. James Hillier & Yuguang Zhao & Loic Carrique & Tomas Malinauskas & Reinis R. Ruza & Tao-Hsin Chang & Gangshun Yi & Helen M. E. Duyvesteyn & Jing Yu & Weixian Lu & Els Pardon & Jan Steyaert & Yanan Zhu, 2024. "Structural insights into Frizzled3 through nanobody modulators," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40213-0. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.