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

Content Provider	Scilit
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.
Copyright Year	2016
Description	Journal: Journal of Biological Chemistry 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 $Phe^{22}$ into a hydrophobic pocket on the GLP-1R.
Related Links	http://www.jbc.org/content/291/30/15778.full.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4957059/pdf http://www.jbc.org/article/S0021925820397118/pdf
Ending Page	15787
Page Count	10
Starting Page	15778
ISSN	00219258
e-ISSN	1083351X
DOI	10.1074/jbc.m116.724542
Journal	Journal of Biological Chemistry
Issue Number	30
Volume Number	291
Language	English
Publisher	Elsevier BV
Publisher Date	2016-07-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology G Protein-coupled Receptor (gpcr) Cyclic Amp (camp) Glucagon-like Peptide-1
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology