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J Biol Chem. 2015 Oct 23;290(43):25782-93. doi: 10.1074/jbc.M115.659797. Epub 2015 Aug 17.

Membrane Curvature-sensing and Curvature-inducing Activity of Islet Amyloid Polypeptide and Its Implications for Membrane Disruption.

Author information

1
From the Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033.
2
the Mork Family Department of Chemical Engineering and Materials Science, University of Southern California, Los Angeles, California 90089, and.
3
the Larry Hillblom Islet Research Center, David Geffen School of Medicine at UCLA, Los Angeles, California 90095.
4
From the Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, langen@usc.edu.

Abstract

Islet amyloid polypeptide (IAPP) is a 37-amino acid amyloid protein intimately associated with pancreatic islet β-cell dysfunction and death in type II diabetes. In this study, we combine spectroscopic methods and microscopy to investigate α-helical IAPP-membrane interactions. Using light scattering and fluorescence microscopy, we observe that larger vesicles become smaller upon treatment with human or rat IAPP. Electron microscopy shows the formation of various highly curved structures such as tubules or smaller vesicles in a membrane-remodeling process, and spectrofluorometric detection of vesicle leakage shows disruption of membrane integrity. This effect is stronger for human IAPP than for the less toxic rat IAPP. From CD spectra in the presence of different-sized vesicles, we also uncover the membrane curvature-sensing ability of IAPP and find that it transitions from inducing to sensing membrane curvature when lipid negative charge is decreased. Our in vivo EM images of immunogold-labeled rat IAPP and human IAPP show both forms to localize to mitochondrial cristae, which contain not only locally curved membranes but also phosphatidylethanolamine and cardiolipin, lipids with high spontaneous negative curvature. Disruption of membrane integrity by induction of membrane curvature could apply more broadly to other amyloid proteins and be responsible for membrane damage observed in other amyloid diseases as well.

KEYWORDS:

circular dichroism (CD); diabetes; electron microscopy (EM); islet amyloid polypeptide; membrane biophysics; protein structure; protein-lipid interaction

PMID:
26283787
PMCID:
PMC4646232
DOI:
10.1074/jbc.M115.659797
[Indexed for MEDLINE]
Free PMC Article

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