Activation of Adhesion G Protein-coupled Receptors: AGONIST SPECIFICITY OF STACHEL SEQUENCE-DERIVED PEPTIDES

Members of the adhesion G protein-coupled receptor (aGPCR) family carry an agonistic sequence within their large ectodomains. Peptides derived from this region, called the sequence, can activate the respective receptor. As the conserved core region of the sequence is highly similar between aGPCRs, t...

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Bibliographic Details
Published in:The Journal of biological chemistry 2017-03, Vol.292 (11), p.4383-4394
Main Authors: Demberg, Lilian M, Winkler, Jana, Wilde, Caroline, Simon, Kay-Uwe, Schön, Julia, Rothemund, Sven, Schöneberg, Torsten, Prömel, Simone, Liebscher, Ines
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Chickens
Chlorocebus aethiops
COS Cells
HEK293 Cells
Humans
Mice
Mutation
Peptides - chemistry
Peptides - pharmacology
Phylogeny
Protein Domains
Receptors, G-Protein-Coupled - agonists
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - genetics
Receptors, G-Protein-Coupled - metabolism
Signal Transduction
Signal Transduction - drug effects
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Summary:Members of the adhesion G protein-coupled receptor (aGPCR) family carry an agonistic sequence within their large ectodomains. Peptides derived from this region, called the sequence, can activate the respective receptor. As the conserved core region of the sequence is highly similar between aGPCRs, the agonist specificity of sequence-derived peptides was tested between family members using cell culture-based second messenger assays. peptides derived from aGPCRs of subfamily VI (GPR110/ADGRF1, GPR116/ADGRF5) and subfamily VIII (GPR64/ADGRG2, GPR126/ADGRG6) are able to activate more than one member of the respective subfamily supporting their evolutionary relationship and defining them as pharmacological receptor subtypes. Extended functional analyses of the sequences and derived peptides revealed agonist promiscuity, not only within, but also between aGPCR subfamilies. For example, the -derived peptide of GPR110 (subfamily VI) can activate GPR64 and GPR126 (both subfamily VIII). Our results indicate that key residues in the sequence are very similar between aGPCRs allowing for agonist promiscuity of several -derived peptides. Therefore, aGPCRs appear to be pharmacologically more closely related than previously thought. Our findings have direct implications for many aGPCR studies, as potential functional overlap has to be considered for and studies. However, it also offers the possibility of a broader use of more potent peptides when the original sequence is less effective.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.763656