Single molecule photobleaching reveals the piecewise arrangement of monomers in IAPP oligomers

Arpan Dey; Sudipta Maiti

doi:10.1117/12.2612694

2 March 2022 Single molecule photobleaching reveals the piecewise arrangement of monomers in IAPP oligomers

Arpan Dey, Sudipta Maiti

Proceedings Volume 11967, Single Molecule Spectroscopy and Superresolution Imaging XV; 119670D (2022) https://doi.org/10.1117/12.2612694
Event: SPIE BiOS, 2022, San Francisco, California, United States

Abstract

Small oligomers are widely accepted to be the major toxic agents in amyloid diseases. However, it is difficult to decipher their structure or conformation. Small oligomers of different sizes are in dynamic equilibrium with each other, and are therefore not amenable to separation techniques. Single molecule approaches can study individual members of an ensemble without separating them. Here we apply a single molecule photobleaching technique, called Q-SLIP (quencher induced step length increase in photobleaching), which allows us to probe the arrangement of monomers in human Islet Amyloid Poly Peptide (hIAPP, or simply IAPP) oligomers. IAPP oligomers are the toxic species associated with Type II diabetes, and understanding the monomer-wise arrangement of membraneattached IAPP oligomers is crucial for understanding the toxic mechanism. QSLIP probes the accessibility of fluorophore labels in each monomer of individual membrane-attached IAPP oligomers. We show that the arrangement is far from uniform. When two monomers form a dimer, the Nterminus of the second monomer gets buried near the middle of the bilayer (which has a doxyl quencher at the 16’ position of the lipid chain). We study oligomers until the tetramer, and our results show that the sequential growth of the oligomers produces a structure very different from a tetrameric subunit of a mature fibril. This may explain the difference in toxicity between the oligomeric species and the fibrils.

Citation Download Citation

Arpan Dey and Sudipta Maiti "Single molecule photobleaching reveals the piecewise arrangement of monomers in IAPP oligomers", Proc. SPIE 11967, Single Molecule Spectroscopy and Superresolution Imaging XV, 119670D (2 March 2022); https://doi.org/10.1117/12.2612694

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