Abstract
The carboxy (C)-termini of G protein coupled receptors (GPCR) dictate essential functions. The KTXXXW motif C-terminus of Frizzleds (FZD) has been implicated in recruitment of Dishevelled (DVL). Through study of FZD4 and its associated ligand Norrin, we report that a minimum of three residues distal to the KTXXXW motif in the C-terminal tail of Frizzled-4 are essential for DVL recruitment and robust Lef/Tcf-dependent transcriptional activation in response to Norrin.
Highlights
The carboxy-terminal tail (C-tail) of G protein coupled receptors (GPCR) plays an essential role in receptor function and biology [1]
Short amphipathic membrane interacting helix VIII at the transmembrane domain 7 (TM7) proximal end of the C-tail of GPCRs has been shown to be critical for G protein coupling and receptor trafficking [4, 5]
A positive correlation was observed between C-tail length and surface expression, the loss in activation was far greater than the apparent loss of some surface expression, suggesting that the simple reduction in cell surface mFZD4 could not account for the more profound loss of its function
Summary
The carboxy-terminal tail (C-tail) of GPCRs plays an essential role in receptor function and biology [1]. Mediating interactions with chaperones and downstream signaling elements, the C-tail may play a role in cell surface expression and downstream signal transduction [2]. Agonists binding to GPCRs have been shown to induce changes in C-tail conformation necessary for activating heterotrimeric G protein [3]. Short amphipathic membrane interacting helix VIII at the transmembrane domain 7 (TM7) proximal end of the C-tail of GPCRs has been shown to be critical for G protein coupling and receptor trafficking [4, 5]. To facilitate efforts in crystallization portions of the C-tail of GPRCs are often times truncated [7, 8]. The flexibility of long unstructured regions of the C-tail required truncation at Corresponding author: Alexander C.
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