Glucagon has a molecular weight of 3,485 Da and is comprised of a single amino acid chain of 29 amino acids that is devoid of disulfide linkages. The amino acid sequence of glucagon is presented in Figure 1. The amino acid sequences of human, rat, rabbit, porcine, bovine, and chicken glucagons indicate that there is a high degree of structural conservation for all these species.

Fig1. Schematic diagram of the proglucagon domain organization in the pancreas and intestine and secretion products from the pancreas (glucagon) and small intestine (GLP-1, GLP-2, and oxyntomodulin peptides). In the pancreas, the secretion of glucagon is strictly regulated by an array of agents. Examples of agonists include neuropeptides, hormones (epinephrine), and amino acids (arginine, glutamine, and alanine). Antagonists of glucagon secretion include glucose and somatostatin. In contrast, in the intestine both glucagon-like peptides (GLP-1 and GLP-2) are secreted by the intestinal L cell. GLP-1 is a potent antihyperglycemic hormone, with a half-life of only 2 minutes, that stimulates glucose-dependent insulin secretion while suppressing glucagon secretion. The actions of GLP-2 are less clear. In the pancreas, proglucagon is processed to secrete intact full-length glucagon (29 amino acids). The “major” proglucagon fragment (amino acid residues 72–158) has no known biological functions. In contrast, in the intestine, proglucagon is designed to secrete (i) oxyntomodulin, a 37 amino acid peptide that contains the 29 amino acid sequence of glucagon followed by an 8 amino acid carboxy-terminal, (ii) glucagon-like peptide-1 (GLP-1), and (iii) glucagon-like-peptide-2 (GLP-2). There is also some information suggesting that the intestinal oxyntomodulin displays weak affinity for the glucagon receptor and may mimic glucagon actions in the pancreas and liver. Portions of this figure came from G.I. Bell et al. Nature B304:368–371 (1983) and J Nutrition, 133: 3709–3711 (2003). The amino acid sequences came with permission from DeGroot, Endocrinology, ch. 35, page 661 (2010).

The secondary and tertiary structures of glucagon have been studied in solution by optical rotary dispersion-circular dichroism and in the crystalline state by X-ray crystallography (3-Å resolution). The full spectrum of biological responses mediated by glucagon is dependent on the presence of each of the 29 amino acids. This is particularly the case when glucagon binding to its receptor activates adenyl kinase. Figure 2 shows the structure of glucagon in solution (panel A)  and an X-ray analysis of glucagon in the crystalline state (panel B). In dilute solutions, the glucagon pep tide, due to its relatively short chain length, is very unstructured and flexible (panel A). The helical region extends from residues 5 to 25 and can result in the formation of two hydrophobic “sticky” patches that are involved in a self-association process which may result in the presence of glucagon dimers.

Fig2. Presentation of the secondary and tertiary structures/shapes of the 29 amino acid residues that constitute glucagon. (A) Key secondary structural characteristics of glucagon shapes in solution. The presence of histidine at the H2N-amino terminus as well as residues #2–5 (magenta) are required for activation of adenyl cyclase, which is key to initiating the biological actions of glycogen in raising blood glucose levels. The position of the amino acid residues shown in black (#5–10) and purple (#28 and 29) are essential for glucagon to bind tightly to its receptor. Two distinct shapes for glucagon in solution are known. Conformation #1 is made up of both β sheets (from residues #5 to 10) and α helices (from #19 to 27). Conformational shape #2 is comprised of all β sheets (#5 to 10) and (#19 to 27). (B) The tertiary X-ray crystallographic shape of glucagon displays the key sites for binding of glucagon to its receptor. This includes the magenta residues (#5 to 10), the blue residues (#22 to 27) and the orange residues (#28 to 29). The two figures were modified from originals prepared at Rutgers University Molecular Anatomy Laboratory by Deepthi Mikkilineni in 2008.

Glucagon’s N-terminal histidine at position #1 (Figure 2; panel B) is essential for its biological activity. The adjacent residues, #2 (serine) and #5 (threonine), are involved in implementing the adenyl cyclase activity which is key to the initiation of glucagon-mediated biological responses. Residues #19–#26 (blue color) have an equal potential to stabilize the structure either as β sheets, or as α-helices. The C-terminal two residues, asparagine (#28) and threonine (#29), increase glucagon’s tight binding to its receptor. Several potent antagonists of glucagon have been synthesized by site-directed mutagenesis; thus deletion of the N-terminal histidine, coupled with substitution of #9 Asp by Glu and α-carboxyamidation of the C-terminal Thr, generates a peptide that binds to the glucagon receptor with high affinity but with no capability to stimulate the production of cAMP.

Thus, the glucagon molecule is unique among medium-sized polypeptides. Although it has a clearly definable secondary structure (α-helix) and quaternary structure (self-association), it has no definable tertiary structure.

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