Functional association of the N-terminal residues with the central region in glucagon-related peptides

GLP‐1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose‐dependent stimulation of insulin secretion. Ex‐4 is a paralog of GLP‐1 that has comparable GLP‐1R potency but extended physiological action. GLP‐1 and Ex‐4 are helical peptides that share ∼50% sequence homo...

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Veröffentlicht in:Journal of peptide science 2011-10, Vol.17 (10), p.659-666
Hauptverfasser: Patterson, James T., Day, Jonathan W., Gelfanov, Vasily M., DiMarchi, Richard D.
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container_title Journal of peptide science
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creator Patterson, James T.
Day, Jonathan W.
Gelfanov, Vasily M.
DiMarchi, Richard D.
description GLP‐1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose‐dependent stimulation of insulin secretion. Ex‐4 is a paralog of GLP‐1 that has comparable GLP‐1R potency but extended physiological action. GLP‐1 and Ex‐4 are helical peptides that share ∼50% sequence homology but differ at several residues, notably the second amino acid which controls susceptibility to DPP‐IV cleavage. This single amino acid difference yields divergent receptor potency when studied in the context of the two hormone sequences. Ex‐4 uniquely tolerates Gly2 through select amino acid differences in the middle region of the peptide that are absent in GLP‐1. We report that substitution of Ex‐4 amino acids Glu16, Leu21, and Glu24 to the GLP‐1 sequence enabled Gly2 tolerance. The coordination of the N‐terminus with these central residues shows an interaction of substantial importance not only to DPP‐IV stability but also to receptor activation. Extension of this observation to glucagon‐based co‐agonist peptides showed different structural requirements for effective communication between the N‐terminus and the mid‐section of these peptides in achieving high potency agonism at the GLP‐1 and GCGRs. Copyright © 2011 European Peptide Society and John Wiley & Sons, Ltd. Biochemical signaling at glucagon‐related peptide receptors is highly dependent on proper orientation of the peptide's N‐terminal histidine within the receptor's core domain. Interactions between the central region (residues 16–24) of the peptide with the receptor extracellular domain appear to influence the orientation of this N‐terminal residue and the acceptance of altered structure at the second amino acid (residue X).
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Extension of this observation to glucagon‐based co‐agonist peptides showed different structural requirements for effective communication between the N‐terminus and the mid‐section of these peptides in achieving high potency agonism at the GLP‐1 and GCGRs. Copyright © 2011 European Peptide Society and John Wiley &amp; Sons, Ltd. Biochemical signaling at glucagon‐related peptide receptors is highly dependent on proper orientation of the peptide's N‐terminal histidine within the receptor's core domain. 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Peptide Sci</addtitle><description>GLP‐1 is an incretin peptide involved in the regulation of glucose metabolism and the glucose‐dependent stimulation of insulin secretion. Ex‐4 is a paralog of GLP‐1 that has comparable GLP‐1R potency but extended physiological action. GLP‐1 and Ex‐4 are helical peptides that share ∼50% sequence homology but differ at several residues, notably the second amino acid which controls susceptibility to DPP‐IV cleavage. This single amino acid difference yields divergent receptor potency when studied in the context of the two hormone sequences. Ex‐4 uniquely tolerates Gly2 through select amino acid differences in the middle region of the peptide that are absent in GLP‐1. We report that substitution of Ex‐4 amino acids Glu16, Leu21, and Glu24 to the GLP‐1 sequence enabled Gly2 tolerance. The coordination of the N‐terminus with these central residues shows an interaction of substantial importance not only to DPP‐IV stability but also to receptor activation. Extension of this observation to glucagon‐based co‐agonist peptides showed different structural requirements for effective communication between the N‐terminus and the mid‐section of these peptides in achieving high potency agonism at the GLP‐1 and GCGRs. Copyright © 2011 European Peptide Society and John Wiley &amp; Sons, Ltd. Biochemical signaling at glucagon‐related peptide receptors is highly dependent on proper orientation of the peptide's N‐terminal histidine within the receptor's core domain. 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ispartof Journal of peptide science, 2011-10, Vol.17 (10), p.659-666
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subjects Amino Acid Sequence
Amino acid substitution
Amino acids
Animals
CGCR
co-agonist
Communication
Dipeptidyl Peptidase 4 - metabolism
DPP-IV
Ex-4
GLP-1
GLP-1R
glucagon
Glucagon-Like Peptide 1 - chemistry
Glucagon-Like Peptides - chemistry
Glucose metabolism
Homology
Hormones
Humans
Insulin
N-Terminus
Peptides - chemistry
Receptor mechanisms
Receptors, Glucagon - chemistry
Secretion
Sequence Homology, Amino Acid
Venoms - chemistry
title Functional association of the N-terminal residues with the central region in glucagon-related peptides
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