Abstract
The Frizzled (FZD) proteins belong to class F of G protein-coupled receptors (GPCRs) and are essential for various pathways involving the secreted lipoglycoproteins of the wingless/int-1 (WNT) family. A WNT-binding cysteine-rich domain (CRD) in FZDs is N-terminally located and connected to the seven transmembrane domain-spanning receptor core by a linker domain that has a variable length in different FZD homologs. However, the function and importance of this linker domain are poorly understood. Here we used systematic mutagenesis of FZD6 to define the minimal N-terminal domain sufficient for receptor surface expression and recruitment of the intracellular scaffold protein Dishevelled (DVL). Further, we identified a triad of evolutionarily conserved cysteines in the FZD linker domain that is crucial for receptor membrane expression and recruitment of DVL. Our results are in agreement with the concept that the conserved cysteines in the linker domain of FZDs assist with the formation of a common secondary structure in this region. We propose that this structure could be involved in agonist binding and receptor activation mechanisms that are similar to the binding and activation mechanisms known for other GPCRs.
Highlights
The Frizzled (FZD) proteins belong to class F of G protein– coupled receptors (GPCRs) and are essential for various pathways involving the secreted lipoglycoproteins of the wingless/ int-1 (WNT) family
WNT-induced DEP domain swapping in DVL leads to reduced DVL–FZD interaction, which appears to be an underlying mechanism of low-density lipoprotein receptor– related protein 5/6 (LRP5/6)– based signalosome formation [13, 18]
We focus on FZD6, a receptor that is generally not signaling in collaboration with LRP5/6 to activate WNT/catenin signaling [19]
Summary
The Frizzled (FZD) proteins belong to class F of G protein– coupled receptors (GPCRs) and are essential for various pathways involving the secreted lipoglycoproteins of the wingless/ int-1 (WNT) family. We used systematic mutagenesis of FZD6 to define the minimal N-terminal domain sufficient for receptor surface expression and recruitment of the intracellular scaffold protein Dishevelled (DVL). Our results are in agreement with the concept that the conserved cysteines in the linker domain of FZDs assist with the formation of a common secondary structure in this region To define the role of the extracellular CRD and the linker region for receptor surface expression and functionality toward DVL, we use systematic mutagenesis. Our findings emphasize the functional importance of the linker domain for surface expression of FZDs and receptor function
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