Figure 1

RAMPs modulate receptor function. (a) The CTR alone is a high-affinity receptor for CT, but in the presence of RAMP1, RAMP2 or RAMP3 is a high-affinity receptor for amylin. The RAMP1/CTR complex (AMY₁ receptor) has high affinity for amylin and CGRP, while the RAMP2/CTR (AMY₂ receptor) and RAMP3/CTR (AMY₃ receptor), are high-affinity amylin receptors with lower affinity for related peptides. (b) Schematic representation showing how RAMPs are allosteric proteins that control GPCR behaviour. In particular, RAMPs alter the accessibility of the CTR extracellular domain-binding groove to amylin and CGRP. The affinity of CTR for these ligands is modified by the binding of RAMP. In CTR alone, amylin/CGRP interactions are suboptimal. RAMP alters the CTR-binding-site sufficiently to allow more optimal binding conditions. The diagram also shows how RAMPs have broader scope as allosteric proteins, with potential for altering GPCR properties via the transmembrane bundle and intracellular C-terminus, in addition to the ECD. G proteins are reported to influence RAMP-GPCR pharmacology, and RAMP-GPCR complexes may also influence G protein coupling. Thus, there is likely to be multidirectional allostery, which can explain the broad effects of RAMPs on numerous GPCRs, from pharmacology through to signalling and intracellular trafficking. (c) Crystal structure of the CGRP receptor ECD (CLR/RAMP1) with CGRPanalog ([D³¹, P³⁴, F³⁵]CGRP_27-37, red) bound and selected class B GPCR ligands: CRF (orange), adrenomedullin (AM) (green), GIP (salmon), PTH (cyan) superimposed. (d) Homology model of the AMY₁ receptor ECD (CTR/RAMP1), with residues within the putative peptide-binding site that were selected for Ala mutation shown as red sticks.