title: Multiple allosteric sites are involved in the modulation of insulin-degrading-enzyme activity by somatostatin.
abstract: Somatostatin is a cyclic peptide, released in the gastrointestinal system and the central nervous system, where it is involved in the regulation of cognitive and sensory functions, motor activity and sleep. It is a substrate of insulin-degrading enzyme (IDE), as well as a modulator of its activity and expression. In the present study, we have investigated the modulatory role of somatostatin on IDE activity at 37 °C and pH 7.3 for various substrates [i.e. insulin, β-amyloid (Aβ)1-40and bradykinin], aiming to quantitatively characterize the correlation between the specific features of the substrates and the regulatory mechanism. Functional data indicate that somatostatin, in addition to the catalytic site of IDE (being a substrate), is also able to bind to two additional exosites, which play different roles according to the size of the substrate and its binding mode to the IDE catalytic cleft. In particular, one exosite, which displays high affinity for somatostatin, regulates only the interaction of IDE with larger substrates (such as insulin and Aβ1-40) in a differing fashion according to their various modes of binding to the enzyme. A second exosite, which is involved in the regulation of enzymatic processing by IDE of all substrates investigated (including a 10-25 amino acid long amyloid-like peptide, bradykinin and somatostatin itself, which had been studied previously), probably acts through the alteration of an 'open-closed' equilibrium.
authors: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy.|Interuniversity Consortium for the Research on Chemistry of Metals in Biological Systems, Bari, Italy.
authors: Grazia R
authors: GR
authors: Tundo
authors: Department of Sciences, University of Roma Tre, Italy.
authors: Elena
authors: E
authors: Di Muzio
authors: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy.|Interuniversity Consortium for the Research on Chemistry of Metals in Biological Systems, Bari, Italy.
authors: Chiara
authors: C
authors: Ciaccio
authors: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy.|Interuniversity Consortium for the Research on Chemistry of Metals in Biological Systems, Bari, Italy.
authors: Diego
authors: D
authors: Sbardella
authors: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy.
authors: Donato
authors: D
authors: Di Pierro
authors: Department of Sciences, University of Roma Tre, Italy.|National Institute of Nuclear Physics, Roma Tre Section, Italy.
authors: Fabio
authors: F
authors: Polticelli
authors: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy.|Interuniversity Consortium for the Research on Chemistry of Metals in Biological Systems, Bari, Italy.
authors: Massimo
authors: M
authors: Coletta
authors: Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Italy. stefano.marini@uniroma2.it.|Interuniversity Consortium for the Research on Chemistry of Metals in Biological Systems, Bari, Italy. stefano.marini@uniroma2.it.
authors: Stefano
authors: S
authors: Marini
mesh_terms: D000495:Allosteric Site; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D019476:Insect Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007339:Insulysin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism*; D018411:Spodoptera / Q000201:enzymology / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D016229:Amyloid beta-Peptides; D019476:Insect Proteins; D007328:Insulin; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); D013004:Somatostatin; D007339:Insulysin; D001920:Bradykinin
keywords: Alzheimer's disease; bradykinin; insulin degrading enzyme; somatostatin; β-amyloid