Truncated glucagon-like peptide-1 and exendin-4 α-conotoxin pl14a peptide chimeras maintain potency and α-helicity and reveal interactions vital for cAMP signaling in vitro

Swedberg, Joakim E., Schroeder, Christina I., Mitchell, Justin M., Fairlie, David P., Edmonds, David J., Griffith, David A., Ruggeri, Roger B., Derksen, David R., Loria, Paula M., Price, David A., Liras, Spiros and Craik, David J. (2016) Truncated glucagon-like peptide-1 and exendin-4 α-conotoxin pl14a peptide chimeras maintain potency and α-helicity and reveal interactions vital for cAMP signaling in vitro. Journal of Biological Chemistry, 291 30: 15778-15787. doi:10.1074/jbc.M116.724542

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Author Swedberg, Joakim E.
Schroeder, Christina I.
Mitchell, Justin M.
Fairlie, David P.
Edmonds, David J.
Griffith, David A.
Ruggeri, Roger B.
Derksen, David R.
Loria, Paula M.
Price, David A.
Liras, Spiros
Craik, David J.
Title Truncated glucagon-like peptide-1 and exendin-4 α-conotoxin pl14a peptide chimeras maintain potency and α-helicity and reveal interactions vital for cAMP signaling in vitro
Formatted title
Truncated glucagon-like peptide-1 and exendin-4 α-conotoxin pl14a peptide chimeras maintain potency and α-helicity and reveal interactions vital for cAMP signaling in vitro
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 1083-351X
Publication date 2016-07-22
Year available 2016
Sub-type Article (original research)
DOI 10.1074/jbc.M116.724542
Open Access Status File (Author Post-print)
Volume 291
Issue 30
Start page 15778
End page 15787
Total pages 10
Place of publication Rockville, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
Glucagon-like peptide-1 (GLP-1) signaling through the glucagon-like peptide 1 receptor (GLP-1R) is a key regulator of normal glucose metabolism, and exogenous GLP-1R agonist therapy is a promising avenue for the treatment of type 2 diabetes mellitus. To date, the development of therapeutic GLP-1R agonists has focused on producing drugs with an extended serum half-life. This has been achieved by engineering synthetic analogs of GLP-1 or the more stable exogenous GLP-1R agonist exendin-4 (Ex-4). These synthetic peptide hormones share the overall structure of GLP-1 and Ex-4, with a C-terminal helical segment and a flexible N-terminal tail. Although numerous studies have investigated the molecular determinants underpinning GLP-1 and Ex-4 binding and signaling through the GLP-1R, these have primarily focused on the length and composition of the N-terminal tail or on how to modulate the helicity of the full-length peptides. Here, we investigate the effect of C-terminal truncation in GLP-1 and Ex-4 on the cAMP pathway. To ensure helical C-terminal regions in the truncated peptides, we produced a series of chimeric peptides combining the N-terminal portion of GLP-1 or Ex-4 and the C-terminal segment of the helix-promoting peptide α-conotoxin pl14a. The helicity and structures of the chimeric peptides were confirmed using circular dichroism and NMR, respectively. We found no direct correlation between the fractional helicity and potency in signaling via the cAMP pathway. Rather, the most important feature for efficient receptor binding and signaling was the C-terminal helical segment (residues 22–27) directing the binding of Phe22 into a hydrophobic pocket on the GLP-1R.
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Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 3 times in Thomson Reuters Web of Science Article | Citations
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