Islet Amyloid Polypeptide: Aggregation and Fibrillogenesisin vitroand Its Inhibition
The development of type 2 diabetes mellitus is associated with the dysfunction of b-cells which is correlated to the formation of deposits consisting of the islet amyloid polypeptide (IAPP). The process of human IAPP (hIAPP) self-association, the intermed
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Islet Amyloid Polypeptide: Aggregation and Fibrillogenesis in vitro and Its Inhibition Janine Seeliger and Roland Winter
Abstract The development of type 2 diabetes mellitus is associated with the dysfunction of β-cells which is correlated to the formation of deposits consisting of the islet amyloid polypeptide (IAPP). The process of human IAPP (hIAPP) selfassociation, the intermediate structures formed as well as the interaction of hIAPP with membrane systems seem to be responsible for the cytotoxicity. For monomeric hIAPP, a natively random coil conformation with transient α-helical parts could be determined in bulk solution, which rapidly converts to an amyloid structure consisting of cross β-sheets. By comparing the amyloidogenic propensities of hIAPP in the bulk and in the presence of various neutral and charged lipid bilayer systems as well as biological membranes, an enhancing effect of anionic and heterogeneous membranes to hIAPP fibril formation has been found. We also discuss the crossinteraction of hIAPP with other amyloidogenic peptides (e.g., insulin and Aβ) and present first small-molecule inhibitors of the fibrillation process of hIAPP. Keywords Islet amyloid polypeptide · Type 2 diabetes mellitus · Aggregation · Model biomembranes · Small-molecule inhibitors
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Introduction
The chronic and cell degenerative type 2 diabetes mellitus (T2DM) comprises 90 % of the 220 million people with diabetes around the world. Islet amyloid deposits are found in the pancreatic Islets of Langerhans of a substantial proportion of all the individuals suffering from this disease. Other common features are a reduced mass of insulin-producing β-cells linked to an insufficient insulin secretion and a decreased insulin sensitivity of peripheral tissues (Hull et al. 2004; Westermark 2011). The deposition of amyloid aggregates in T2DM was already described in 1901 (Opie 1901; Weichselbaum and Stangl 1901). However, further insights into the mechanism of amyloid formation and its contribution to the pathogenesis of the R. Winter () · J. Seeliger Faculty of Chemistry, Physical Chemistry I-Biophysical Chemistry, TU Dortmund University, Otto-Hahn Str. 6, D-44227, Dortmund, Germany e-mail: [email protected]; [email protected]
J. R. Harris (ed.), Protein Aggregation and Fibrillogenesis in Cerebral and Systemic Amyloid Disease, Subcellular Biochemistry 65, DOI 10.1007/978-94-007-5416-4_8, © Springer Science+Business Media Dordrecht 2012
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Fig. 8.1 Intracellular processing of prepro islet amyloid polypeptide (preproIAPP) in islet β-cells. Processing is initiated by formation of a disulfide bond at the ER and cleavage of the N-terminal signal peptide after transport of preproIAPP to the trans-Golgi network. The COOH-terminal propeptide of the resulting proIAPP is cleaved preferentially by PC1/3. PC2 enzymes are removing the N-terminal propeptide of proIAPP in the secretory vesicles. The remaining basic residues at the C-terminus are removed by the action of CPE, which
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