title: Modulation of human IAPP fibrillation: cosolutes, crowders and chaperones.
abstract: The cellular environment determines the structure and function of proteins. Marginal changes of the environment can severely affect the energy landscape of protein folding. However, despite the important role of chaperones on protein folding, less is known about chaperonal modulation of protein aggregation and fibrillation considering different classes of chaperones. We find that the pharmacological chaperone O4, the chemical chaperone proline as well as the protein chaperone serum amyloid P component (SAP) are inhibitors of the type 2 diabetes mellitus-related aggregation process of islet amyloid polypeptide (IAPP). By applying biophysical methods such as thioflavin T fluorescence spectroscopy, fluorescence anisotropy, total reflection Fourier-transform infrared spectroscopy, circular dichroism spectroscopy and atomic force microscopy we analyse and compare their inhibition mechanism. We demonstrate that the fibrillation reaction of human IAPP is strongly inhibited by formation of globular, amorphous assemblies by both, the pharmacological and the protein chaperones. We studied the inhibition mechanism under cell-like conditions by using the artificial crowding agents Ficoll 70 and sucrose. Under such conditions the suppressive effect of proline was decreased, whereas the pharmacological chaperone remains active.
authors.affiliation: Department of Physical Chemistry II, Ruhr-University Bochum, 44780 Bochum, Germany. simon.ebbinghaus@rub.de.
authors.forename: Mimi
authors.initials: M
authors.lastname: Gao
authors.forename: Kathrin
authors.initials: K
authors.lastname: Estel
authors.forename: Janine
authors.initials: J
authors.lastname: Seeliger
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Friedrich
authors.forename: Susanne
authors.initials: S
authors.lastname: Dogan
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.forename: Roland
authors.initials: R
authors.lastname: Winter
authors.forename: Simon
authors.initials: S
authors.lastname: Ebbinghaus
mesh_terms: D002942:Circular Dichroism; D003911:Dextrans / Q000737:chemistry / Q000378:metabolism; D005362:Ficoll / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism*; D010078:Oxazines / Q000737:chemistry / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism; D011392:Proline / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D000683:Serum Amyloid P-Component / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013395:Sucrose / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D003911:Dextrans; D058228:Islet Amyloid Polypeptide; D018832:Molecular Chaperones; C569778:O4 compound; D010078:Oxazines; D000683:Serum Amyloid P-Component; D005362:Ficoll; D011092:Polyethylene Glycols; D013395:Sucrose; D011392:Proline