Structure-Function Analysis of RAMP1-RAMP3 Chimeras

T Qi, John Simms, RJ Bailey, Mark Wheatley, DL Rathbone, DL Hay, DR Poyner

Research output: Contribution to journalArticle

6 Citations (Scopus)


The role of receptor activity modifying protein I (RAMP1) in forming receptors with the calcitonin receptor-like receptor (CLR) and the calcitonin receptor (CTR) was examined by producing chimeras between RAMP1 and RAMP3. RAMPs have three extracellular helices. Exchange of helix I of the RAMPS or residues 62-69 in helix 2 greatly reduced CLR trafficking (a marker for CLR association). Modeling suggests that these exchanges alter the CLR recognition site oil RAMP], which is more exposed than oil RAMP3. Exchange of residues 86-89of RAMP1 had no effect on the trafficking of CLR but reduced the potency Of (h) alpha CGRP and adrenomedulin. However, these alterations to RAMP1 had no effect oil the potency of h beta CHRP. These residues of RAMP1 lie at the junction of helix 3 and its connecting loop with helix 2. Modeling suggests that (lie loop is more exposed in RAMP1 than RAMP3; it may play an important role in peptide building, either directly or indirectly. Exchange of residues 90-94 of RAM PI Caused a modest reduction in CLR expression and a 15-fold decrease in CGRP potency. It is unlikely that the decrease in expression Is enough to explain the reduction in potency, and so these may have dual roles in recognizing CLR and CGRP. For CTR, only 6 Out of 26 chimeras covering the extracellular part of RAMP1 did not reduce agonist potency. Thus the association of CTR with RAMP1 seems more sensitive to changes in RAMP I Structure induced by the chimeras than is CLR.
Original languageEnglish
Pages (from-to)522-531
Number of pages10
Issue number3
Publication statusPublished - 1 Jan 2010


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