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

Lukas Grätz, Maria Kowalski-Jahn, Magdalena M. Scharf, Pawel Kozielewicz, Michael Jahn, Julien Bous, Nevin A. Lambert, David E. Gloriam and Gunnar Schulte ()
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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
Julien Bous: Sec. Receptor Biology & Signaling
Nevin A. Lambert: Augusta University
David E. Gloriam: University of Copenhagen
Gunnar Schulte: Sec. Receptor Biology & Signaling

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40213-0

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