Interspecies Variation Affects IAPP Membrane Binding

Abstract

The aggregation of islet amyloid polypeptide (IAPP) is associated with beta-cell dysfunction in type 2 diabetes (T2D) in humans. One possible mechanism of toxicity is the interaction of IAPP oligomers with lipid membranes to disrupt bilayer integrity and/or homeostasis of the cell. Amino acid sequence variations of IAPP between species can greatly decrease their propensity for aggregation. For example, human IAPP is toxic to beta-cells, but rat and pig IAPP are not. However, it is not clear how these differences affect membrane association. Using native mass spectrometry with lipid nanodiscs, we explored the differences in the association of human, rat, and pig IAPP with lipid bilayers. We discovered that human and rat IAPP bound nanodiscs with anionic dipalmitoyl-phosphatidylglycerol (DPPG) lipids, but pig IAPP did not. Furthermore, human and rat IAPP interacted differently with the membrane. Human IAPP shows potential tetramer complexes, but rat IAPP associated with the membrane sequentially. Thus, overall IAPP-bilayer interactions are not necessarily related to disease, but differences in oligomeric behavior at the membrane may instead play a role.

What’s the defect? Using mass defects to study oligomerization of membrane proteins and peptides in nanodiscs with native mass spectrometry

“…For example, with pIAPP, a low-level contaminant was present in all samples that was disregarded due to its presence in the control. 94 Another challenge with mass defect analysis can be the loss of labile interactions. Although native MS is gentle enough to preserve noncovalent interactions, fragile interactions are sometimes disrupted inside the instrument.…”