KissWiki Basic Biology Structural elements of Gpr-54 (Kisspeptin receptor)
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Gpr-54 is a member of the rhodopsin-like or Class A family of G-protein coupled receptors located on human chromosome 19p13.3. GPCRs are membrane bound receptors that contain seven hydrophobic transmembrane domains each containing between 25-40 amino acids.
The transmembrane (TM) domains form α-helices of unequal length that can extend beyond the lipid bi-layer, and these form a counter clockwise barrel shape perpendicular to the membrane (Fig. 8). Of these domains TM II, IV and VII are the most hydrophobic as they contain only one hydrophilic residue, whereas the other domains contain a mixture of hydrophilic and neutral residues. GPCRs also have an extracellular N-terminus and a cytoplasmic C-terminus as well as 3 extracellular loops (EL) and 3 intracellular loops (IL). Each of these loops is between 10-40 amino acids in length except IL3 which can vary in length dramatically and contain up to 150 amino acids. GPCRs also have many conserved residues to ensure receptor activation and signalling. For example, Aspartate in TM II and Asparagine in TM III are conserved to keep TM II and VII in close proximity via hydrogen bonds enabling receptor activation (Ulloa-Aguirre et al., 1999).
Gpr-54 is a typical Class A GPCR in primary structure with an ORF of 1191 base pairs or 396 amino acids. The receptor gene contains 5 exons with 4 introns within TM II (800bp) and III (800bp) and ICL3 (180bp). Gpr-54 also contains many of the conserved residues found in this type of GPCR. Gpr-54 contains the conserved asparagine in TM I, the conserved aspartate in TM II mentioned above and conserved prolines in TM IV-VII. Gpr-54 also contains three consensus sequences for N-linked glycosylation at its N-terminus and a consensus sequence for PKC phosphorylation in IL3. Cysteines involved in the classical N-terminal disulphide bond are located in EL1 and EL2. There are also three possible palmitoylation cysteine sites in the C-terminus (Lee et al., 1999). The C-terminus of gpr-54 has also been shown to be rich in proline and arginine residues corresponding to four overlapping Src homology 3 (SH3) domain structures (Fig. 9). These SH3 domains have been shown to interact with the catalytic subunit of the serine/threonine (Ser/Thr) protein phosphatase, PP2A. The gpr-54/PP2A unit can then modulate phosphorylation of critical signalling intermediates. As PP2A has been shown to be a tumour suppressor this may be a mechanism for gpr-54 mediate inhibition of metastasis, as PP2A is known to up regulate phosphatase and tensin homology (PTEN) to down regulate the tumour promoter, Akt via dephosphorylation of PIP2 (Evans et al., 2008).
GPCRs signal by interacting with heterotrimeric g-proteins to cause conformational changes and an exchange of guanosine diphosphate (GDP) with guanosine triphosphate (GTP), allowing dissociation of Gα from the βγ subunit to activate intracellular signalling. Gpr-54 interacts with the Gαq/11 subunit to activate specific signalling mechanisms (Kotani et al., 2001). Mutations in the receptor, have revealed that this interaction involves Leu148 of IL2 since dissociation of the g-protein subunits is disrupted by mutations at this residue (Wacker et al., 2008). IL2 of gpr-54 forms hydrophobic interactions with the Gα subunit that stabilises the switch II region of the g-protein. This activates the subunit into a conformation that facilitates GDP-GTP exchange, allowing dissociation and maximising downstream signalling. Therefore, IL2 of gpr-54 acts as a guanine nucleotide exchange factor (GEF). Leu148 has been shown to dock in close proximity to the GTPase domain of the Gαq/11, where Pro138 interaction causes a change in IL2 to allow Phe139 to fit into the hydrophobic grove created by α2/β4 and α3/β5 loops of the g-protein (Wacker et al., 2008). Phe139 can then interact with Phe220, Val223, Trp263 and Phe264 of the switch II region. This is now thought to be a mechanism common to all GPCR class A receptors.
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