Type
Text
Type
Thesis
Advisor
Carrico, Isaac | Raleigh, Daniel P | Miller, Lisa.
Date
2013-12-01
Keywords
Chemistry | Amylin, Islet amyloid polypeptide, S20G, type 2 diabetes
Department
Department of Chemistry.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/77080
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Islet amyloid polypeptide (IAPP) is a 37 residues long polypeptide hormone. IAPP is co-secreted with insulin by the B-cells in the pancreas and is stored with insulin in secretory vesicles. IAPP helps to maintain glucose homeostasis in the body by regulating glucagon secretion. IAPP is one of the most amyloidogenic peptide known, and IAPP amyloid formation plays a role in type 2 diabetes. IAPP amyloid formation contributes to B-cells dysfunction and B-cells loss in islets. There is one known naturally found IAPP mutant; the serine 20 to glycine (S20G) mutant weakly increases the risk of early onset diabetes in Asian populations. In vitro studies provided the evidence that the S20G mutant accelerates amyloid formation. This thesis research is about the molecular mechanism of accelerating amyloid formation by the S20G mutant. Studies with D-amino acid mutants at position 20 confirm that increased rate of amyloid formation by S20G mutant is not the result as of unusual backbone conformation adopted by serine 20 in the wild type peptide. Experiments using helical prone natural and unnatural amino acid substitution show that enhanced amyloid formation by the S20G mutant is not the result of a steric clash or the relief of unfavorable hydrogen bond interactions that slow amyloid formation in wild type IAPP. Analysis of a S19G mutant confirms the specific amyloidogenic profile of the S20G mutant. Seeding studies suggests that the single point mutations do not cause significant changes in final fibril structure. | 103 pages
Recommended Citation
Akter, Rehana, "Accelerating Amyloid Formation by Islet Amyloid Polypeptide" (2013). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2917.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2917