Conformational studies on the pancreatic polypeptide hormone family

Abstract

(Rcceiwd bcbrtiat-! 27. 19x4) ~ L J B 83 0215 Pancreatic polypeptide has been extracted and sequenced from a wide range of species. The 36-residue polypeptides have some hormonal characteristics, and show a high degree of sequence homology. Two recently isolated polypeptides, from porcine gut and brain, also show a high degree of sequence homology with the pancreatic polypeptides. It was proposed that these polypeptides were members of a related family.The X-ray determined structure of one member of the family, turkey pancreatic polypeptide, is known to high resolution, but there is no structural information for the others. Studies designed to give an insight into the tertiary structure of these related molecules have been carried out, including model building using interactive computer graphics, circular dichroic spectroscopy and secondary structure prediction using a variety of algorithms.The results indicate that a compact globular conformation, similar to that observed in turkey pancreatic polypeptide may be adopted by all molecules and that this may be more highly conserved than the individual amino acid sequences.Since the first identification of pancreatic polypeptide (PP) in the chicken pancreas [l], homologous peptides have been isolated from the alligator (Kimmel, unpublished results), the turkey [2], goose (Shen et al., unpublished results), ox, pig, sheep, dog and human [3]. These 36-residue polypeptides share a feature common to many gastroenteric hormones, a blocked. amidated carboxy terminus. Tatemoto and Mutt [4] used this feature to isolate possible hormonal peptides in tissue extracts and isolated, amongst others, two peptides, PYY from pig intestine [5] and NPY from pig brain tissue [6]. They showed that these polypeptides have considerable homology with the pancreatic polypeptides and proposed that PP, NPY and PYY form a newly recognised hormone family (see Table 1).The structure of one member of this family, turkey pancreatic polypeptide, has been determined by X-ray crystallography [2, 7, 81 and the analysis recently extended to very high resolution, d,,, = 98pm [9-111. The turkey PP protomer comprises of two segments of secondary structure: a polyproline type-I1 helix (residues 1-8) and an a-helix (residues 14-32). These helices, joined by a type-I1 fl-turn, interact via hydrophobic contacts to produce a compact and stable tertiary fold. The C-terminal region, residues 33 -36, extend away from the body of the molecule and display some flexibility in the crystal lattice. Further hydrophobic interactions are achieved by the formation of dimers in which a cage of aromatic residues, related by the crystallographic diad axis, is formed. In the crystal the dimers form extended oligomeric arrays via the coordination of a zinc ion. The zinc coordination involves His-34 Nt: of one, Asp-23 of another and the glycine nitrogen and carbonyl oxygen of a third dimer. The penta-,4hhrericr/ions. PP, pancreatic polypeptide; NPY, pig neuropolypcptide; PYY, pig intestinal polypeptide. coordinated site is c...

Effects of various neuropeptide Y/peptide YY fragments on electrically‐evoked contractions of the rat vas deferens

“…PYY 1-36 was somewhat more potent than NPY 1-36, P < 0.01. There was a tendency for the shorter PYY fragments to have progressively lower pIC50 values, and PYY 1-36 was more potent than any of these fragments ( (Glover et al, 1985). Both these parts are highly conserved among the …”

“…members of the PP family (Glover et al, 1985). Recently, a potent NPY agonist was synthesized by linking NPY 1-4 via epsilon-aminocapronic acid to the C-terminal peptide amide segment 25-36 (Beck et al, 1989).…”

Structure/activity relationships of C‐terminal neuropeptide Y peptide segments and analogues composed of sequence 1–4 linked to 25–36

“…The starting conformation of simulation 1 was generated by converting the crystal structure of avian pancreatic polypeptide [42] into the structure of neuropeptide Y-(I -4-Ahx-25 -36)-peptide. The programs INSIGHT and MOLEDT from Biosym were used for these manipulations.…”

“…Since no polar solvent molecules were included in the calculations, this energy difference merely reflects the loss of van der Waals contacts and hydrogen bonds. However it can be assumed that the interaction with water molecules would be even more favourable for the folded conformation of neuropeptide Y-(1 -4-Ahx-25 -36)-peptide since it is known that hydrophobic contacts between the amphiphilic a-helix and the N-terminal polyproline helix are the driving force for the folding of avian pancreatic polypeptide and neuropeptide Y [42]. At least some of these hydrophobic interactions are still preserved in neuropeptide Y-(1 -4-Ahx-25 -36)-peptide.…”

Broad spectrum antibiotic activity of skin‐PYY

“…They possess common features of tertiary structure, known as the PP-fold [3]. The PP-fold, as characterized by X-ray diffraction analysis of crystals, consists of two antiparallel helices: an N-terminal polyproline helix spanning residues 1-14, and a long amphipathic Cterminal alpha-helix.…”