ArticleThe Journal of biological chemistry2016
Calcitonin and Amylin Receptor Peptide Interaction Mechanisms: INSIGHTS INTO PEPTIDE-BINDING MODES AND ALLOSTERIC MODULATION OF THE CALCITONIN RECEPTOR BY RECEPTOR ACTIVITY-MODIFYING PROTEINS.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 75 citations in OpenAlex.
- [Research progress on the role of calcitonin gene-related peptide in the repair of diabetic wounds].Zhonghua shao shang yu chuang mian xiu fu za zhi · 2026Review
- Functional characterisation of dura mater αCGRP degradation fragments at vascular, immune, and CGRP receptor targets.The journal of headache and pain · 2026Article
- Molecular Mechanisms of Islet Amyloid Polypeptide Aggregation: Towards Chemical Strategies to Prevent Amyloid Formation and to Design Non-Aggregating Peptide Therapeutics.International journal of molecular sciences · 2026Review
- The story of amylin: from physiology to therapy.Nature metabolism · 2026Review
- Structural and mechanistic insights into dual activation of cagrilintide in amylin and calcitonin receptors.Acta pharmacologica Sinica · 2026Article
- Amylin receptor subunit interactions are modulated by agonists and determine signaling.Science signaling · 2025Article
- Amylin Receptor 1 Mutagenesis Revealed a Potential Role of Calcitonin Serine 29 in Receptor Interaction.Biomedicines · 2025Article
- Characterization of the Two-Domain Peptide Binding Mechanism of the Human CGRP Receptor for CGRP and the Ultrahigh Affinity ssCGRP Variant.Biochemistry · 2025Article
- Extracellular bimolecular fluorescence complementation for investigating membrane protein dimerization: a proof of concept using class B GPCRs.Bioscience reports · 2024Article
- Review
- Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins.Pharmacological reviews · 2023Review
- Discovery of potential biomarkers for osteoporosis using LC/GC-MS metabolomic methods.Frontiers in endocrinology · 2023Article
- Sustained Activation of CLR/RAMP Receptors by Gel-Forming Agonists.International journal of molecular sciences · 2022Article
- Pramlintide: A Novel Therapeutic Approach for Osteosarcoma through Metabolic Reprogramming.Cancers · 2022Article
- Gel-forming antagonist provides a lasting effect on CGRP-induced vasodilation.Frontiers in pharmacology · 2022Article
- β-Cell Death in Diabetes: Past Discoveries, Present Understanding, and Potential Future Advances.Metabolites · 2021Review
- Antistress Action of Melanocortin Derivatives Associated with Correction of Gene Expression Patterns in the Hippocampus of Male Rats Following Acute Stress.International journal of molecular sciences · 2021Article
- Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors.Biomolecules · 2021Article
- A selective role for receptor activity-modifying proteins in subchronic action of the amylin selective receptor agonist NN1213 compared with salmon calcitonin on body weight and food intake in male mice.The European journal of neuroscience · 2021Article
- Asn-linked N-acetylglucosamine of the amylin receptor 2 extracellular domain enhances peptide ligand affinity.FEBS open bio · 2021Article
Corrections and comments
- Erratum issued
Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Receptor activity-modifying proteins (RAMP1-3) determine the selectivity of the class B G protein-coupled calcitonin receptor (CTR) and the CTR-like receptor (CLR) for calcitonin (CT), amylin (Amy), calcitonin gene-related peptide (CGRP), and adrenomedullin (AM) peptides. RAMP1/2 alter CLR selectivity for CGRP/AM in part by RAMP1 Trp-84 or RAMP2 Glu-101 contacting the distinct CGRP/AM C-terminal residues. It is unclear whether RAMPs use a similar mechanism to modulate CTR affinity for CT and Amy, analogs of which are therapeutics for bone disorders and diabetes, respectively. Here, we reproduced the peptide selectivity of intact CTR, AMY1 (CTR·RAMP1), and AMY2 (CTR·RAMP2) receptors using purified CTR extracellular domain (ECD) and tethered RAMP1- and RAMP2-CTR ECD fusion proteins and antagonist peptides. All three proteins bound salmon calcitonin (sCT). Tethering RAMPs to CTR enhanced binding of rAmy, CGRP, and the AMY antagonist AC413. Peptide alanine-scanning mutagenesis and modeling of receptor-bound sCT and AC413 supported a shared non-helical CGRP-like conformation for their TN(T/V)G motif prior to the C terminus. After this motif, the peptides diverged; the sCT C-terminal Pro was crucial for receptor binding, whereas the AC413/rAmy C-terminal Tyr had little or no influence on binding. Accordingly, mutant RAMP1 W84A- and RAMP2 E101A-CTR ECD retained AC413/rAmy binding. ECD binding and cell-based signaling assays with antagonist sCT/AC413/rAmy variants with C-terminal residue swaps indicated that the C-terminal sCT/rAmy residue identity affects affinity more than selectivity. rAmy(8-37) Y37P exhibited enhanced antagonism of AMY1 while retaining selectivity. These results reveal unexpected differences in how RAMPs determine CTR and CLR peptide selectivity and support the hypothesis that RAMPs allosterically modulate CTR peptide affinity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.