期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 26, 页码 22894-22904出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.215814
关键词
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资金
- American Diabetes Association [1-10-BS-04]
- National Institutes of Health National Center for Research Resources [1S10RR016760]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1024908] Funding Source: National Science Foundation
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-beta 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 beta-cells.
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