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STRUCTURAL FEATURES AND MODIFIERS OF ISLET AMYLOID
POLYPEPTIDE: IMPLICATIONS FOR TYPE II DIABETES MELLITUS
by
Sahar Bedrood
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
August 2009
Copyright 2009 Sahar Bedrood
Object Description
| Title | Structural features and modifiers of islet amyloid polypeptide: implications for type II diabetes mellitus |
| Author | Bedrood, Sahar |
| Author email | bedrood@usc.edu; carpemane@graffiti.net |
| Degree | Doctor of Philosophy |
| Document type | Thesis |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2009-05-07 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-06-23 |
| Advisor (committee member) |
Haworth, Ian Chen, Jeannie Chow, Robert |
| Abstract | Protein misfolding is a common motif in a number of human diseases, including Alzheimer disease, Parkinson disease and type II diabetes mellitus (TTDM). In TTDM, over 90% of patients are found to have pancreatic amyloid deposits upon autopsy. These deposits are primarily composed of a 37-residue human islet amyloid polypeptide (hIAPP). Evidence suggests an association between these amyloid plaques and pancreatic beta-cell dysfunction. Elucidating the structure of these deposits and the effects modifiers have on the misfolding pathway can help further the understanding of its toxicity and could be of use in the design of drug inhibitors for amyloid diseases. I used site-directed spin-labeling and electron paramagnetic resonance (EPR) spectroscopy to analyze spin-labeled derivatives of hIAPP to determine structural features of the peptide in its fibrillar form. Using continuous-wave EPR and four-pulse DEER coupled with computational modeling, I determined a detailed structural model of hIAPP fibrils. The N-terminal and C-terminal regions are less ordered and more mobile and there is a turn region between residues 19-30 located between two β-strands (13-18 and 31-36). My findings also show that the β1 and β2 strands from one molecule of hIAPP are staggered in relation to one another. The staggered peptide stacks directly on another staggered peptide, forming a protofilament with a twist that I aptly call a β-spiral motif. In addition to these structural findings, I have studied the effects of modifiers, such as curcumin and annexin proteins, to the misfolding of amyloid fibrils. Using EPR, ThT and EM, I found that these molecules or proteins seem to alter hIAPP, Aβ and α-synuclein fibril formation and fibril morphology. Additionally, studies of these modifiers in tissue culture and animal models showed reduced toxicity and protein aggregation.; Both the identification of hIAPP structure and the role of amyloid modifiers can give way to therapeutic intervention of amyloid diseases. |
| Keyword | IAPP; islet amyloid polypeptide; amyloid; protein misfolding; type II diabetes mellitus; amyloid structure; curcumin; annexin V |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2315 |
| Rights | Bedrood, Sahar |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Bedrood-2945 |
| Archival file | uscthesesreloadpub_Volume56/etd-Bedrood-2945.pdf |
Description
| Title | Page 1 |
| Full text | STRUCTURAL FEATURES AND MODIFIERS OF ISLET AMYLOID POLYPEPTIDE: IMPLICATIONS FOR TYPE II DIABETES MELLITUS by Sahar Bedrood A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) August 2009 Copyright 2009 Sahar Bedrood |
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