WEHI Wednesday Seminar hosted by Associate Professor Alisa Glukhova

Dr Wessel Burger
Senior Research Officer – Glukhova Laboratory, Structural Biology division, WEHI

Unusual G protein coupling at Frizzled Receptors

 

Davis Auditorium

Join via SLIDO enter code #WEHIWednesday

Including Q&A session
 

Frizzled receptors are cell surface receptors that mediate Wnt signalling, an evolutionarily conserved pathway that controls embryonic development, tissue regeneration, and adult stem cell homeostasis. Although Frizzled receptors are structurally classified as G protein–coupled receptors (GPCRs), Wnt signal transduction predominantly occurs through the activation of the intracellular effector Dishevelled rather than through G proteins. This structural classification has fuelled longstanding debate over whether Frizzled receptors directly couple to and signal through G proteins, given the limited evidence supporting such interactions.

Here, we present cryo–electron microscopy structures of Frizzled receptors in complex with heterotrimeric G proteins, determined in multiple membrane-mimetic environments, including detergent micelles and lipid nanodiscs. Collectively, these structures reveal that Frizzled receptors engage G proteins through a unique interface compared to other GPCRs. Complementary mutagenesis, signalling assays and molecular dynamics simulations further demonstrate how this unconventional coupling mode begins to resolve the longstanding conundrum surrounding Frizzled receptors and their relationship to G protein signalling.

All welcome!