The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Fang, Z.; Chen, S.; Pickford, P.; Broichhagen, J.; Hodson, D.; Correa, I. R.; Kumar, S.; Gorlitz, F.; Dunsby, C.; French, P.; Rutter, G. A.; Tan, T.; Bloom, S. R.; Tomas, A.; Jones, B.

doi:10.1101/2020.02.24.961524

bioRxiv · 10.1101/2020.02.24.961524

The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists

Fang, Z.·Chen, S.·Pickford, P.·Broichhagen, J.·Hodson, D.·Correa, I. R.·Kumar, S.·Gorlitz, F.·Dunsby, C.·French, P.·Rutter, G. A.·Tan, T.·Bloom, S. R.·Tomas, A.·Jones, B.

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Abstract

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 signalling, endocytosis and recycling, dependent both on the introduction of a His [->] Phe switch at position 1 and the specific mid-peptide 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/961524v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@cb425borg.highwire.dtl.DTLVardef@719e37org.highwire.dtl.DTLVardef@14a45b9org.highwire.dtl.DTLVardef@127afd1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Fang, Z., Chen, S., Pickford, P., Broichhagen, J., Hodson, D., Correa, I. R., Kumar, S., Gorlitz, F., Dunsby, C., French, P., Rutter, G. A., Tan, T., Bloom, S. R., Tomas, A., Jones, B.. 2020-02-25. The influence of peptide context on signalling and trafficking of glucagon-like peptide-1 receptor biased agonists. https://doi.org/10.1101/2020.02.24.961524

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