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Cnidarian fluorescent proteins detect and inhibit amyloid fibril formation and discovering novel peptide inhibitors
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Authors
Xu, Changmingzi
Issue Date
2017-08
Type
Electronic thesis
Thesis
Thesis
Language
en_US
Keywords
Biology
Alternative Title
Abstract
Many monomeric and soluble peptides or proteins are able to self-assemble into amyloid fibrils which have an ordered β-strand structure through changes in pH, solvent and temperature. Amyloid fibrils are associated with at least fifty diseases including HIV infectivity enhancement, Alzheimer's disease and Type II diabetes. Increasing evidence suggests that pre-fibrillar species may be toxic to cells. Given the pathological significance of amyloid-related species, detection and inhibition of amyloid fibril formation will provide insights on developing biological diagnostic tools and therapeutics. Cnidarian fluorescent derived proteins such as Green Fluorescent Protein (GFP) and mCherry have been used to monitor gene expression and protein localization through biological imaging. In this work, we discovered that GFP and mCherry can specifically bind amyloid fibrils formed from natural peptides and proteins, a small molecule, and synthetic peptides. They do not bind other fibrillar structures such as microtubules or F-actins and also do not bind to amorphous aggregates. GFP and mCherry can also bind small aggregates formed during the lag phase and early elongation phase of fibril formation and do not bind to the corresponding soluble monomers. The binding to amyloid fibrils can be mediated by electrostatic interactions. In addition to being useful for fibril detection, GFP can also inhibit semen-based amyloid fibril formation in a dose-dependent manner. The inhibition is possibly due to GFP binding to amyloid fibrils and oligomeric species and thus preventing the elongation of the fibril. We also discovered two peptides that can inhibit semen-based amyloid fibril formation. This discovery may provide insights on designing short peptide-based amyloid fibril inhibitors as therapeutics for amyloid-related disease.
Description
August2017
School of Science
School of Science
Full Citation
Publisher
Rensselaer Polytechnic Institute, Troy, NY