Mechanism of Amylin Fibrillization Enhancement by Heparin

We characterized the interaction of amylin with heparin fragments of defined length, which model the glycosaminoglycan chains associated with amyloid deposits found in type 2 diabetes. Binding of heparin fragments to the positively charged N-terminal half of monomeric amylin depends on the concentra...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-07, Vol.286 (26), p.22894-22904
Main Authors: Jha, Suman, Patil, Sharadrao M., Gibson, Jason, Nelson, Craig E., Alder, Nathan N., Alexandrescu, Andrei T.
Format: Article
Language:English
Subjects:
Amyloid
Animals
Cell Line
Diabetes
Diabetes Mellitus, Type 2 - metabolism
Extracellular Matrix
FRET
Glycosaminoglycan
Heparan Sulfate Proteoglycans
Heparin
Heparin - chemistry
Heparin - metabolism
Humans
IAPP
Insulin-Secreting Cells - chemistry
Insulin-Secreting Cells - metabolism
Islet Amyloid Polypeptide
Islet Amyloid Polypeptide - chemistry
Islet Amyloid Polypeptide - metabolism
Mice
Models, Biological
Molecular Biophysics
Oligosaccharides - chemistry
Oligosaccharides - metabolism
Protein Structure, Quaternary
Protein Structure, Secondary
TIRFM
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Summary:We characterized the interaction of amylin with heparin fragments of defined length, which model the glycosaminoglycan chains associated with amyloid deposits found in type 2 diabetes. Binding of heparin fragments to the positively charged N-terminal half of monomeric amylin depends on the concentration of negatively charged saccharides but is independent of oligosaccharide length. By contrast, amylin fibrillogenesis has a sigmoidal dependence on heparin fragment length, with an enhancement observed for oligosaccharides longer than four monomers and a leveling off of effects beyond 12 monomers. The length dependence suggests that the negatively charged helical structure of heparin electrostatically complements the positively charged surface of the fibrillar amylin cross-β structure. Fluorescence resonance energy transfer and total internal reflection fluorescence microscopy experiments indicate that heparin associates with amylin fibrils, rather than enhancing fibrillogenesis catalytically. Short heparin fragments containing two- or eight-saccharide monomers protect against amylin cytotoxicity toward a MIN6 mouse cell model of pancreatic β-cells.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.215814