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figure 7-8 Three-dimensional structure of the monomeric form of insulin oriented perpendicular to the 3-fold axis. The side chains of all of the amino acids are shown; the A chain is dark gray and the B chain in light gray. The dashes indicate an important region on the surface of the insulin monomer that is believed to contact the receptor. [Reproduced with permission of B. Xiao, University of York, York, UK.]

figure 7-8 Three-dimensional structure of the monomeric form of insulin oriented perpendicular to the 3-fold axis. The side chains of all of the amino acids are shown; the A chain is dark gray and the B chain in light gray. The dashes indicate an important region on the surface of the insulin monomer that is believed to contact the receptor. [Reproduced with permission of B. Xiao, University of York, York, UK.]

groups of residues B-24 and B-26, which form an antiparallel pleated sheet structure (see Figure 7-9). The hexameric structure of crystalline insulin consists of three dimers ordered around a major 3-fold axis containing two zinc atoms, each coordinated at the imidazole groups of three B-10 histidine residues (see Figure 7-9). Indeed, the propensity for insulin to crystallize into hexamers may be related to the regular arrays seen in the electron microscopic evaluation of the storage granules of the /3-cell.

While for many years it was thought that insulin was not a member of any hormone family, either in a structural sense (e.g., oxytocin and vasopressin are structural analogs of one another) or in a protein-processing sense (proopiomelanocortin produces (3-lipotropin, ACTH, endorphins, etc.), it now appears that there is a hormone family of homologous growth factors that includes proteins with regions of amino acid sequences identical to that of insulin. These include the following: (i) relaxin, a polypeptide hormone from the corpus luteum that is responsible for the dilation of the symphysis pubis prior to parturition; (ii) insulin-like growth factors (IGFs) I or II (formerly known as NSILA or nonsuppressible insulin-like activity); (iii) somatomedins (particularly somatomedin C); and (iv) nerve growth factor (NGF). Some of these factors are discussed in further detail in Chapter 19.

B. Glucagon

Glucagon, which is secreted by the a-cells of the pancreas, has a molecular weight of 3450. It is the most potent hepatic glycogenolytic agent known. The amino acid sequence of glucagon is presented in Figure 7-10. In contrast to insulin, glucagon is composed of a single amino acid chain of 29 residues and is devoid of disulfide linkages. The amino acid sequences of rat, rabbit, human, porcine, bovine, turkey, chicken, and duck glucagons have been determined. There is a high degree of structural conservation in all of these peptides.

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-A resolution). In dilute solutions, the glucagon peptide, due to its relatively short chain length, is flexible, with many different conformations and some indication of a stable interaction between valine-23 and tryptophan-25. In more concentrated solutions and in the crystalline state, the molecules self-associated into a-helical trimers. The helical region extends from residues 10 to 25 and results in the formation of two hydrophobic "sticky" patches that are involved in the self-association process. Thus, the glucagon molecule is unique among medium-sized polypeptides. Although it has a clearly definable secondary structure (a helix) and quaternary structure (self-association), it has no definable tertiary structure.

From biological studies, it has been determined that virtually the entire glucagon peptide chain is required for optimal interaction with the glucagon-sensitive adenylate cyclase of hepatocyte membranes. The evidence suggests that glucagon binds to its receptor as a consequence of entropic considerations, resulting in the selection of the optimal solution helical conformer, which has an available hydrophobic region for stereoselective interaction with the membrane receptor.

Several potent antagonists of glucagon have been synthesized by site-directed mutagenesis; thus deletion of the N-terminal histidine, coupled with substitution of Asp9 by Glu and a-carboxyamidation of the C-terminal Thr, generates a peptide that binds to the glucagon receptor with high affinity but that does not stimulate the production of cAMP.

Glucagon is also structurally homologous with a family of peptide hormones found in the gastrointestinal tract (see Chapter 8); these include secretin, vaso-

Monomer

Hexamer

Hexamer

Dimer Tetramer

Dimer Tetramer

FIGURE 7-9 Hexameric, dimeric, and monomeric forms of insulin, showing the development of dimers from monomers and their organization into the hexamer. [The insulin structures were obtained courtesy of G. G. Dodson (York University, York, UK) and redrawn by F. D. Coffman and M. F. Dunn (University of California, Riverside).]

FIGURE 7-9 Hexameric, dimeric, and monomeric forms of insulin, showing the development of dimers from monomers and their organization into the hexamer. [The insulin structures were obtained courtesy of G. G. Dodson (York University, York, UK) and redrawn by F. D. Coffman and M. F. Dunn (University of California, Riverside).]

active intestinal polypeptide (VIP), gastric inhibitory peptide (GIP), enteroglucagon (a 69-amino-acid peptide that has all 34 amino acids of glucagon at its N-terminus), and glicentin (a 100-amino-acid peptide isolated from the intestine). Interestingly, glicentin has many of the immunodeterminants of glucagon and can account for much of the glucagon-like activity of the intestine.

C. Pancreatic Polypeptide

Pancreatic polypeptide (PP) is a 36-amino-acid peptide that appears to stimulate the gastric secretion of HC1 and pepsin; it may also act as a satiety factor. PP is known to be released after a protein meal.

The amino acid sequences of several PP are given in Figure 7-11. All sequenced PP have amidated carboxy-termini. With the exception of the avian PP, which has 20 out of 36 residues different from those of human PP, there is strict conservation of sequences (only 2-3 amino acid differences) among the other four sequenced PP species.

Like insulin, PP molecules can self-associate to dimers and, in the presence of zinc ions, can form higher oligomers. Because a homologous polypeptide has been isolated from pig intestine, it has been proposed that PP may be a member of a larger family of pancreatic and gastroenteric hormones.

PP belongs to a family of structurally related carbox-yamidated neuroendocrine peptides; these include

Human H2N- HSQGTFTSDYSKYLDSRRAQOFVQWLMNT -COOH

FIGURE 7-10 Primary amino acid sequence of human glucagon.

Human APLEPQYPGDDATPEQMAQYAADLKKY I NMLTRPRY -COOH Porcine APLEPVYPGDDATPEQMAQYAAELKKY I NMLTRPRY -COOH Avian G P S_Q P I Y P G D D A P_V E A_L I R E Y D N L Q_Q YLNV_VTRHRY -COOH

figure 7-11 Primary amino acid sequences of human, porcine, and avian pancreatic polypeptides (PP). Amino acids underlined are different from those of human glucagon. [Data are derived from Kimmel, J. R., Pollock, H. G., Chance, R. E., Johnson, M. G„ Reeve, J. R., Jr., Taylor, I. L., Miller, C., and Shivery, J. E. (1984). "Pancreatic polypeptide from rat pancreas." Endocrinology 114, 1725-1731.]

neuropeptide Y (NPY) and peptide YY (PYY), which are found in many neurons of the central and peripheral nervous systems (see Table 8-1).

D. Somatostatin

Somatostatin is the smallest of the pancreatic hormones; it contains 14 amino acids and one disulfide bridge. Somatostatin is derived from a 116-amino-acid preprosomatostatin (see Figure 7-12). Although somatostatin was originally discovered in the hypothalamus, it is also known to be produced by the S-cells of the endocrine pancreas and dispersed cells in the gastrointestinal tract. Somatostatin, when produced by the hypothalamus, is frequently termed growth hormone release-inhibiting hormone (GIF).

The physiological role of circulating somatostatin is not clear; it may function in a paracrine fashion to regulate pancreatic islet functions.

E. Islet Amyloid Polypeptide

A second peptide hormone that is produced by the pancreatic /3-cells is islet amyloid polypeptide (IAPP) or amyloid (see Figure 7-13). IAPP is a 37-amino-acid

I-«-Preprosomatostatin (116 aa)-

I-«-Preprosomatostatin (116 aa)-

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