Amyloidogenic Propensity of ProIAPP and IAPP in the Presence of Negatively Charged Lipid Bilayers

Abstract

The islet amyloid polypeptide (IAPP) is synthesized in the β-cells of the pancreas from its precursor, the proislet amyloid polypeptide (ProIAPP). ProIAPP is co-processed in the secretory granules, and then co-secreted to the extracellular matrix together with insulin. As indicated earlier, partially processed N-terminal ProIAPP is able to interact with negatively charged moieties, like heparan sulfate, which may lead to islet amyloid plaque formation. Amyloid plaques have been found both extracellularly and intracellularly in type II diabetic patients. Here, we studied the amyloidogenic propensity of native ProIAPP and compared it with that of IAPP in the absence and presence of negatively charged membranes. Our CD studies show that the secondary structure content of ProIAPP and IAPP is predominantly unordered with small amounts of ordered secondary structure elements as confirmed by ATR-FTIR spectroscopy. However, in the presence of anionic membranes, ProIAPP forms predominantly α-helices and loops that subsequently transform to intermolecular β-sheet structures. For comparison, IAPP forms intermolecular β-sheets largely via unordered and loop structures. The ATR-FTIR and fluorescence spectroscopy studies performed also reveal that ProIAPP has a higher amyloidogenic propensity in the presence of negatively charged membranes, but is still less amyloidogenic than IAPP. AFM studies have also been carried out which show that ProIAPP, at variance to IAPP, does not form long fibrils, but rather protofilaments or short fibrils, only. Hence, both, the presence of a small amount of unprocessed ProIAPP in β-cell secretion, or the interaction with negatively charged surfaces, like negatively charged lipid bilayers, may initiate islet amyloid plaque formation.