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...
SynopsisThe 36-amino acid avian pancreatic polypeptide has been studied by x-ray analysis a t 0.98-A resolution and refined using a restrained least-squares technique to an agreement factor of 15.6%. The polypeptide, which has a compact globular structure with a hydrophobic core, comprises a polyproline-like helix (residues 2-8) and an a-helix (residues 14-32). The molecule forms symmetrical dimers linked through zinc atoms in the crystal lattice. The high-resolution analysis defines sequence-dependent distortions in the a-helical parameters due to hydrogen bonding of water molecules and side chains. The thermal parameters indicate an increased flexibility of the main chain at the turn between the helices and in the C-terminal residues. For the first time, six-parameter anisotropic thermal ellipsoids have been refined for each atom; these define the directions of the molecular motions in the polypeptide, indicating concerted vibrations. The physiological roles of conformation, flexibility, and dynamics of this polypeptide hormone are discussed.
Two crystal structures of deamino-oxytocin have been determined at better than 1.1A resolution from isomorphous replacement and anomalous scattering x-ray measurements. In each of two crystal forms there are two closely related conformers with disulfide bridges of different chirality, which may be important in receptor recognition and activation.
The initial steps of carbon assimilation and photorespiration are catalysed by ribulose-1,5-bisphosphate carboxylase/oxygenase (EC 4.1.1.39). Natural variation in the kinetic properties of the enzyme suggest that it is possible to alter the enzyme to favour the carboxylation activity relative to oxygenation. Mutagenesis in vitro of the gene encoding the large subunit of the enzyme from Anacystis nidulans has been used to modify catalytic properties. Residues at the C-terminal end of loop 6 of the β/α barrel structure of the large subunit influence specificity towards the gaseous substrates, CO2 and O2. None of the residues altered by mutagenesis appear to interact directly with the transition state analogue and their effect on the reaction of the enediolate intermediate with the gaseous substrates and stabilization of the resulting transition state intermediates by lysine 334 must be indirect. Interactions with other parts of the enzyme must also be important in determining substrate specificity. Backbone carbonyl groups close to lysine 334 interact with lysine 128; mutation of lysine 128 to residues of less positive polarity reduces enzyme activity and favours oxygenation relative to carboxylation. The likely effects on assimilation rates of altering the kinetic properties of Rubisco have been modelled. A leaf with cyanobacterial Rubisco may out-perform a higher plant Rubisco at elevated CO2 and cool temperatures.
RDS is part of the Home Office. The Home Office's purpose is to build a safe, just and tolerant society in which the rights and responsibilities of individuals, families and communities are properly balanced and the protection and security of the public are maintained.RDS is also a part of the Government Statistical Service (GSS). One of the GSS aims is to inform Parliament and the citizen about the state of the nation and provide a window on the work and performance of government, allowing the impact of government policies and actions to he assessed. Therefore -Research Development and Statistics Directorate exists to improve policy making, decision taking and practice in support of the Home Office purpose and aims, to provide the public and Parliament with information necessary for informed debate and to publish information for future use. AcknowledgementsThis has been a complex research study and many people have provided us with valuable assistance.We are especially grateful to Include (formerly Cities in Schools) which provided us with access to a sample of young people permanently excluded from school. Martin Stephenson, Chief Executive of Include, Rachel Pope, Kath Pinnock and past and present project managers at Include co-operated with us and supported the project throughout. The police services, local authority youth justice sections and education departments who work with Include were also extremely helpful. Further support in accessing offending data was provided by the Home Office Research and Statistics Department.In Luton, we are grateful to the Luton Youth Offending Team and Luton Education Department for their input to the research study, and to Mark Radley of Social Software for his advice and help with youth offending databases. Thanks as well to colleagues at the University of Luton, Ian Toon and Dani Agbewu-Lokku who helped with fieldwork and data processing.Accessing offending data proved to be an extremely challenging task, and we are grateful to Dr Carol Hayden and Tim Martin for providing us with information regarding their work on offending careers and school exclusion. Although it has not proved possible to use this in the final report, their time and the quality of their work were extremely helpful in enabling us to develop our analysis.Throughout the study we have appreciated the support and advice forthcoming from the Home Office, and especially that provided -at different times -by John Graham, Julie Vennard, Diane Caddle, Claire Flood-Page and Vicki Harrington.Finally, we would like to thank the 28 young people and the parents we interviewed, who gave their time and shared their experiences in the hope that this research would have a positive influence on the experiences of other young people excluded from school.Any errors are, of course, the responsibility of the authors.ii achieved higher-level qualifications felt that they were having to work harder in order to compensate for their past. vii viii the young person's life, in regard to family circumstances, educational experience...
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