Hot topic: FZD6 dimers dissociate after stimulation – briefly

GPCRs of all classes are widely thought to form homodimers, heterodimers and higher-order oligomers. The functional significance of dimerization is well understood for Class C receptors but less certain for the other GPCR classes, including the rather unconventional class F or Frizzled (FZD) receptors. Although the relationship between receptor activity and quaternary structure is often unclear, across classes it is generally found that ligand binding does not dramatically influence dimerization. A recent report by Gunnar Schulte and his colleagues suggests that in this respect class F receptors may once again be somewhat different [1]. Using an impressive combination of live-cell imaging, biochemical and modeling techniques the group presents evidence that FZD6 forms relatively stable dimers that dissociate when stimulated with the activating ligand WNT-5A. Remarkably, FZD6 protomers reassociate at the cell surface after 20 minutes of continuous stimulation, a timing which coincides with termination of ERK1/2 phosphorylation. Taken together with previous results from the Schulte group [2] the data are consistent with a model where FZD6 dimers are constitutively associated with G proteins and the phosphoprotein Disheveled (DVL) in an inactive state complex that must dissociate in order to generate downstream signals. Although it remains to be seen how representative this model will be for other GPCRs, including other class F receptors, the report sets an important standard for studies aimed at linking receptor activity and quaternary structure.

Comments by Nevin A. Lambert, PhD, Department of Pharmacology and Toxicology Medical College of Georgia, Augusta University, USA

[1] Petersen, J., Wright, S.C. et al. (2017) Agonist-induced dimer dissociation as a macromolecular step in G protein-coupled receptor signaling. Nat Commun. 8(1):226.  [PMID: 28790300]

[2] Kilander, M.B.C., Petersen, J. et al. (2014) Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6. FASEB J. 28(5):2293-305. [PMID: 24500924]

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