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

Grätz, L., Kowalski-Jahn, M., Scharf, M. M., Kozielewicz, P., Jahn, M., Bous, J., et al. (2023). Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations. Nat Commun, 14(1), 4573. doi:10.1038/s41467-023-40213-0.

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Item Permalink: https://hdl.handle.net/21.11116/0000-000D-82CF-7 Version Permalink: https://hdl.handle.net/21.11116/0000-000D-CAEA-8
Genre: Journal Article

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 Creators:
Grätz, Lukas, Author
Kowalski-Jahn, Maria, Author
Scharf, Magdalena M., Author
Kozielewicz, Pawel, Author
Jahn, Michael1, Author
Bous, Julien, Author
Lambert, Nevin A., Author
Gloriam, David E., Author
Schulte, Gunnar, Author
Affiliations:
1Max Planck Unit for the Science of Pathogens, Max Planck Society, ou_3213696              

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 Abstract: Abstract

The class Frizzled of G protein-coupled receptors (GPCRs), consisting of ten Frizzled (FZD
1-10
) 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 FZD
5
for signal specification. Similar data were obtained for FZD
4
and FZD
10
suggesting that our findings can be extrapolated to other members of the FZD family. Comparative molecular dynamics simulations of wild type and selected FZD
5
mutants further support the concept that distinct conformational changes in FZDs specify the signal outcome. In conclusion, we find that FZD
5
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.

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 Dates: 2023-07
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/s41467-023-40213-0
BibTex Citekey: gratz_pathway_2023
 Degree: -

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Title: Nat Commun
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 14 (1) Sequence Number: - Start / End Page: 4573 Identifier: ISSN: 2041-1723