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Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration

Melissa Birol, Sunil Kumar, Elizabeth Rhoades, Andrew D. Miranker
doi: https://doi.org/10.1101/095158
Melissa Birol
1Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520
2Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104
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Sunil Kumar
3Department of Chemistry, New York University, Silver Center for Arts and Science, 100 Washington Square East, 10th Floor, New York, NY 10003
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Elizabeth Rhoades
2Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA 19104
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  • For correspondence: andrew.miranker@yale.edu elizabeth.rhoades@sas.upenn.edu
Andrew D. Miranker
1Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Avenue, New Haven, CT 06520
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  • For correspondence: andrew.miranker@yale.edu elizabeth.rhoades@sas.upenn.edu
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Summary

Peptide mediated gain-of-toxic function is central to pathology in Alzheimer’s, Parkinson’s and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here, we focus on islet amyloid polypeptide (IAPP) mediated loss of insulin secreting cells in diabetics. Newly developed methods enable structure-function inquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two class of pores coexist; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilizing non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalizable approach for inquiry applicable to other partially ordered protein assemblies.

Highlights

  • The peptide amyloid precursor, IAPP, forms two classes of membrane porating oligomers.

  • The two classes have a >100-fold difference in pore size with the large pore form correlated with mitochondrial depolarization and toxicity.

  • A drug-like molecule distinguishes between the two oligomer classes and rescues toxicity by stabilizing non-toxic poration without displacing IAPP from the mitochondria.

  • The mechanism of pore-forming oligomer assembly includes stepwise coalescence of smaller, dynamic assemblies.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 23, 2017.
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Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration
Melissa Birol, Sunil Kumar, Elizabeth Rhoades, Andrew D. Miranker
bioRxiv 095158; doi: https://doi.org/10.1101/095158
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Structurally distinct oligomers of islet amyloid polypeptide mediate toxic and non-toxic membrane poration
Melissa Birol, Sunil Kumar, Elizabeth Rhoades, Andrew D. Miranker
bioRxiv 095158; doi: https://doi.org/10.1101/095158

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