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Modulation of human IAPP fibrillation: cosolutes, crowders and chaperones

Item Type:Article
Title:Modulation of human IAPP fibrillation: cosolutes, crowders and chaperones
Creators Name:Gao, M., Estel, K., Seeliger, J., Friedrich, R.P., Dogan, S., Wanker, E.E., Winter, R. and Ebbinghaus, S.
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.
Keywords:Atomic Force Microscopy, Circular Dichroism, Dextrans, Ficoll, Fluorescence Spectrometry, Fourier Transform Infrared Spectroscopy, Islet Amyloid Polypeptide, Molecular Chaperones, Oxazines, Polyethylene Glycols, Proline, Secondary Protein Structure, Serum Amyloid P-Component, Sucrose, Thermodynamics
Source:Physical Chemistry Chemical Physics
Publisher:Royal Society of Chemistry
Page Range:8338-8348
Date:7 April 2015
Official Publication:https://doi.org/10.1039/c4cp04682j
PubMed:View item in PubMed

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