The Influence of Peptide Context on Signaling and
Trafficking of Glucagon-like Peptide‑1 Receptor Biased Agonists
Zijian Fang
Shiqian Chen
Philip Pickford
Johannes Broichhagen
David J. Hodson
Ivan R. Corrêa
Sunil Kumar
Frederik Görlitz
Chris Dunsby
Paul M. W. French
Guy A. Rutter
Tricia Tan
Stephen R. Bloom
Alejandra Tomas
Ben Jones
10.1021/acsptsci.0c00022.s001
https://acs.figshare.com/articles/journal_contribution/The_Influence_of_Peptide_Context_on_Signaling_and_Trafficking_of_Glucagon-like_Peptide_1_Receptor_Biased_Agonists/12037491
Signal
bias and membrane trafficking have recently emerged as important
considerations in the therapeutic targeting of the glucagon-like peptide-1
receptor (GLP-1R) in type 2 diabetes and obesity. In the present study,
we have evaluated a peptide series with varying sequence homology
between native GLP-1 and exendin-4, the archetypal ligands on which
approved GLP-1R agonists are based. We find notable differences in
agonist-mediated cyclic AMP signaling, recruitment of β-arrestins,
endocytosis, and recycling, dependent both on the introduction of
a His → Phe switch at position 1 and the specific midpeptide
helical regions and C-termini of the two agonists. These observations
were linked to insulin secretion in a beta cell model and provide
insights into how ligand factors influence GLP-1R function at the
cellular level.
2020-03-26 20:45:26
Peptide Context
insulin secretion
midpeptide helical regions
membrane trafficking
ligand factors influence GLP -1R function
beta cell model
GLP -1R
β- arrestins
agonist-mediated cyclic AMP
position 1
archetypal ligands
sequence homology
glucagon-like peptide
type 2 diabetes
GLP -1R agonists
peptide series