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The crystal structure of avian pancreatic polypeptide (aPP), a 36-residue polypeptide with some hormonal properties, has been determined by using single isomorphous replacement and anomalous scattering to 2.1-A resolution. The phases were extended to 1.4-A resolution by using a modified tangent formula. The molecule contains two regions ofsecondary structurean extended polyproline-like helix (residues 1-8) and an a-helix (residues 14-31) -that run roughly antiparallel. The packing together of nonpolar groups from these regions gives the molecule a hydrophobic core in spite of its small size. The aPP molecules form a symmetrical dimer in the crystal stabilized principally by interlocking of nonpolar groups from the a-helices. The aPP dimers are crosslinked by coordination ofZn"+; three aPP molecules contribute ligands to each zinc. The coordination geometry is a distorted trigonal bipyramid. The properties of the aPP molecule in solution are consistent with expectations based on the crystal structure. The aPP molecule has several general features in common with the pancreatic hormones insulin and glucagon. All three hormones have complex mechanisms for self-association. Like insulin, aPP seems to have a stable monomeric structure but its biological activity seems to depend on the more flexible COOH-terminal region analogous to the flexible NH2-terminal region of glucagon.Pancreatic polypeptide (PP) is a 36-amino acid peptide found in the endocrine pancreas (1, 2). There is close sequence homology among the mammalian peptides although mammalian and avian PPs differ at about 20 positions (Fig. 1). All sequences have an amidated COOH terminus, a feature known to occur in other polypeptide hormones such as gastrin, secretin, and oxytocin (3). There is now evidence that PP is synthesized as a larger precursor, in the same way as other pancreatic polypeptide hormones (4).The ultrastructural appearance ofthe PP-producing cells also strongly argues for an endocrine function for this peptide. PP is located in membrane-enclosed granules (5) like those of the alpha and beta pancreatic cells in which glucagon and insulin are synthesized. The PP cells are located on the periphery of the islets at the head of the pancreas, to the exclusion of glucagon cells which occur at the periphery of the islets of the tail end (6). In certain fishes such as the teleost Cottus scorpius, which has two principal islets, the pyloric region has mainly PP cells and the splenic contains no PP cells (7).PP is released into the circulation partly as a result of vagal cholinergic stimulation after feeding or in response to hypoglycemia. Although the half-life is of the order of 5 min the levels remain increased for several hours, indicating a continuous release (8). Injections ofbovine PP (bPP) decrease food intake and body weight in the hyperglycemic ob/ob mouse (9), and injections of either the bovine or avian PP (aPP) cause New Zealand obese mice to revert to normal (10). Although these observations indicate that PP may act as a satiety...

A model for the three-dimensional structure of insulin-like growth factor (IGF) is proposed based on the close sequence homology of IGF with insulin, the tertiary structure of which is known. The IGF molecule is postulated to have an insulin-like main chain conformation for residues equivalent to B6-B27 and A1-A21 and a hydrophobic core nearly identical to that of insulin. A short connecting peptide of twelve residues and an extension at the COOH-terminus are easily accommodated on the molecular surface. MATERIALS AND METHODS The model was built in several stages. The proposed structure was first constructed using Lapquip model parts at a scale of 1 cm = 1 A. This was examined for unfavorable intramolecular contracts and readjusted before the coordinates of each atom were read off using a mechanical device. The approximate coordinates were then regularized using the "modelfit" computer program of Isaacs et al (12), and bond lengths and angles and other intramolecular distances were calculated using an IBM 360/65 computer. The model was then displayed on a computer graphics system (Digital Equipment Corp. graphics with a PDPll computer) using programs written by D. Richardson, P. Pauling, and C. Chothia, and adjustments were made using the interactive facilities of the graphics system to optimize the intramolecular distances. Finally, the model was regeometricized using "modelfit" and stereo pairs of the model were generated in hard copy. RESULTS AND DISCUSSIONThree-dimensional model for IGF I Table 1 shows the sequences of human IGF I, IGF II, and porcine insulin aligned so that the maximum homology is obtained. The numbering for the insulin A and B chains is indicated, as is the numbering for the IGF I polypeptide. The sequence of the IGF connecting peptide of 12 residues is also included, but because this shows no homology with the proinsulin connecting peptide, the latter is omitted. IGF I has an extension of eight residues at the COOH terminus of the A chain. Table 2 gives the differences in numbers of amino acids between the 51 amino acids of porcine insulin and the equivalent residues of other insulins, the protein hormone relaxin (13)(14)(15), which also appears to be homologous with insulin, and IGF.The sequence comparison shows a close homology for residues 5-25 of IGF (B6-B26 of insulin) and 42-61 (A1-A20). The arrangement of cystines is identical in IGF and insulin, and glycines 7 (B8), 19 (B20), and 22 (B23), which have dihedral angles that are disallowed for residues with side chains, are conserved, so that the polypeptide backbone can assume the same three-dimensional structure as insulin. We began by building the sequence 5-26 and 42-61 into an insulin-like structure. This conformation is shown schematically in Fig. 1. Residues 8-18 (B9-B19) and [43][44][45][46][47][48] (A2-A7) are right-handed a-helices and residues 54-60 (A13-A19) formed a less organized right-handed helix. Cys 47 and 52 (A6 and All) and Cys 61 and 18 (A20 and B19) have their disulfides placed in the core, while the Cys ...

Pentraxins, which include C reactive protein (CRP) and serum amyloid P component (SAP), are prototypic acute phase reactants that serve as indicators of inflammatory reactions. Here we report genomic and cDNA cloning of mouse ptx3 (mptx3), a member of the pentraxin gene family and characterize its extrahepatic expression in vitro and in vivo. mptx3 is organized into three exons on chromosome 3: the first (43 aa) and second exon (175 aa) code for the signal peptide and for a protein portion with no high similarity to known sequences the third (203 aa) for a domain related to classical pentraxins, which contains the “pentraxin family signature.” Analysis of the N terminal portion predicts a predominantly alpha helical structure, while the pentraxin domain of ptx3 is accommodated comfortably in the tertiary structure fold of SAP. Normal and transformed fibroblasts, undifferentiated and differentiated myoblasts, normal endothelial cells, and mononuclear phagocytes express mptx3 mRNA and release the protein in vitro on exposure to interleukin-1beta (IL-1beta) and tumor necrosis factor (TNF)alpha. mptx3 was induced by bacterial lipopolysaccharide in vivo in a variety of organs and, most strongly, in the vascular endothelium of skeletal muscle and heart. Thus, mptx3 shows a distinct pattern of in vivo expression indicative of a significant role in cardiovascular and inflammatory pathology.

Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common 'insulin fold' is probably adopted by all family members. Although the specificities of receptor binding are different, there is a possibility of co-evolution of polypeptides and their receptors.

The structures of [Met5]enkephalin (Tyr-GlyGly-Phe-Met) and [Leu5]enkephalin (Tyr-Gly-Gly-Phe-Leu) have been determined from single crystal x-ray diffraction data and refined to residuals of 0.100 and 0.092, respectively. The [Met5]enkephalin structure consists of dimers forming antiparallel a-sheets extending in the monoclinic ac plane with 10.6 water molecules per dimer. The two molecules, related by pseudo two-fold axes, have similar backbone conformations and similar tyrosine and phenylalanine side-chain conformations. Both methionine residues are disordered and the disorder is different in the two independent molecules. Additional hydrogen bonds connect adjacent dimers to form infinite sheets normal to the b axis. The water molecules are found mainly in the interstices between the sheets. [Leu5]Enkephalin crystallizes as a monohydrate that is isomorphous with the [Met5]enkephalin structure with respect to the a-sheet but different with respect to the tyrosine and phenylalanine side-chain conformations and water content. The peptide chains in both structures are fully extended and more nearly planar than pleated. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

A model for the evolution of insulin mainly in terms of adaptive processes is discussed. The model depends critically on the relationship of sequence changes to the three-dimensional structure and the role of various parts of this structure in the conversion of the proinsulin molecule to the active form, the storage of insulin, its transport to the site of action and its interaction with a receptor.

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