Sites of interaction between calcitonin-family peptides and their receptors

The calcitonin-family of peptides comprises calcitonin, amylin, calcitonin gene-related peptides (CGRPs), adrenomedullin (AM) and AM2. Their receptors are calcitonin receptorlike receptor (CLR) or calcitonin receptor (CTR) and receptor activity-modifying protein (RAMP) complexes. RAMP1 with CLR constitutes the CGRP receptor whereas RAMP2 or 3 with CLR generates the AM receptors. Amylin receptors are formed from CTR interactions with RAMPs. The association of RAMPs with CLR or CTR can alter receptor trafficking, pharmacology or/and signalling capabilities. Despite the broad pharmacological potential as drug targets for treatments of diseases such as diabetes, migraine and osteoporosis, the calcitonin peptide family receptors are not fully characterised. This is mainly due to the difficulty in the structural determination and the complexity of the interaction system. To generate drugs that target these receptors, a clearer understanding of the role of each receptor component in peptide binding is needed. In the thesis, structure-function relationships of residues or regions in the extracellular N termini of RAMPs were determined aiming to identify residues or regions that are important for ligand to receptor interactions for the calcitonin family peptides. The data generated have emphasised the importance of helices 2 and 3 of RAMP to peptide to receptor interactions. In particular, E74 of RAMP3 has been demonstrated to be crucial for high affinity binding and high potency response of AM at the AM₂ receptor. In addition, a naturally occurring variant of the human CTR lacking the N-terminal 47 amino acids has been characterised in this thesis. For the first time, it has been shown that this truncated variant is still able to form a functional amlyin receptor with RAMP1 at the cell surface. The observation of reduced potency for some peptide ligands at the truncated CTR suggests that the truncated region may contain some residues that are involved in the interactions for these peptides. In summary, the findings in this thesis have contributed to our understanding of the ligand to receptor interactions for the calcitonin family peptides. Residues and regions identified in this thesis could potentially provide some targeting points for future investigations for rational drug design.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biological Sciences

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2011

Author dc:creator

• Qi, Tao

Advisors dc:contributor.advisor

• Hay, D
• Glass, M

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/6666

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/6666