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pH dependence of amylin fibrillization
Suman Jha1, Jessica M Snell, Sarah R Sheftic
1Department of Molecular and Cell Biology, University of Connecticut , Storrs, Connecticut 06269-3125, United States.
Biochemistry
|January 1, 2014
Summary
Amylin misfolding in type 2 diabetes is pH-dependent. His18
Area of Science:
- Biochemistry
- Molecular Biology
- Endocrinology
Background:
- Type 2 diabetes is characterized by the misfolding of the hormone amylin into amyloid plaques.
- This misfolding process is implicated in the destruction of pancreatic beta-cells, which are crucial for insulin production.
- Amylin misfolding is influenced by pH, making the study of its ionizable residues critical.
Purpose of the Study:
- To determine the pKa values of the ionizable residues in amylin.
- To investigate the role of these residues in amylin fibrillization and cytotoxicity.
- To understand the pH-dependent nature of amylin aggregation.
Main Methods:
- Studied pH dependence of fibrillization in amylin variants with single ionizable groups.
- Measured pKa values of the alpha-amino group and His18.
- Utilized thioflavin T dye, Nile Red, and turbidimetry to monitor fibrillization.
Main Results:
- The alpha-amino group has a pKa of ~8.0, consistent with random coil models.
- His18 in fibrils exhibits a lowered pKa of 5.0 (vs. 6.5 in random coil) due to a hydrophobic environment and electrostatic repulsion.
- Charged His18 inhibits fibrillization and reduces cytotoxicity in a beta-cell model.
Conclusions:
- His18 functions as an electrostatic switch, regulating amylin fibrillization.
- The pKa of His18 is significantly affected by its environment within amylin fibrils.
- Understanding these pKa values and their impact is vital for potential therapeutic strategies targeting amylin aggregation in type 2 diabetes.
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