Resolving the unconventional mechanisms underlying RXFP1 and RXFP2 receptor function.
The receptors for relaxin and insulin-like peptide 3 (INSL3) are now well-characterized as the relaxin family peptide (RXFP) receptors RXFP1 and RXFP2, respectively. They are G-protein-coupled receptors (GPCRs) with closest similarity to the glycoprotein hormone receptors, with both containing large ectodomains with 10 leucine-rich repeats (LRRs). Additionally, RXFP1 and RXFP2 are unique in the LGR family in that they contain a low-density lipoprotein class A (LDL-A) module at their N-terminus. Ligand-mediated activation of RXFP1 and RXFP2 is a complex process involving various domains of the receptors. Primary ligand binding occurs via interactions between B-chain residues of the peptides with specific residues in the LRRs of the ectodomain. There is a secondary binding site in the transmembrane exoloops which may interact with the A chain of the peptides. Receptor signaling through cAMP then requires the unique LDL-A module, as receptors without this domain bind ligand normally but do not signal. This is an unconventional mode of activation for a GPCR, and the precise mode of action of the LDL-A module is currently unknown. The specific understanding of the mechanisms underlying ligand-mediated activation of RXFP1 and RXFP2 is crucial in terms of targeting these receptors for future drug development.
Hartley
Brigham J
BJ
Howard Florey Institute, University of Melbourne, Parkville, Victoria, Australia.
Scott
Daniel J
DJ
Callander
Gabrielle E
GE
Wilkinson
Tracey N
TN
Ganella
Despina E
DE
Kong
Chze K
CK
Layfield
Sharon
S
Ferraro
Tania
T
Petrie
Emma J
EJ
Bathgate
Ross A D
RA
D001665:Binding Sites; D006801:Humans; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000378:metabolism*; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism*
C417543:RXFP1 protein, human; C472867:RXFP2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide