Domains in islet amyloid polypeptide important in fibril formation and toxicity
department or school: Medicine, Faculty of
department or school: Pathology and Laboratory Medicine, Department of
data provider: DSpace
degree campus: UBCV
creator: Park, Kirily
issued: 2009-11-17T00:00:00
issued: 2003
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Islet amyloid deposits are a characteristic pathologic lesion o f the pancreas in type 2 diabetes and are composed primarily of the islet beta cell peptide islet amyloid polypeptide (IAPP or amylin). Islet amyloid fibrils are toxic to insulin-producing beta cells. Heparan sulfate proteoglycans (HSPGs) are also a component of islet amyloid in vivo and accelerate amyloid fibril formation in vitro. Although the cause of amyloid formation in pancreatic islets is unknown, HSPGs have been proposed to play an initiating role. Impaired processing of proIAPP, the IAPP precursor, has also been implicated in the mechanism of islet amyloid formation. The N - and C-terminal cleavage sites at which proIAPP is processed by prohormone convertases contain series of basic amino acid residues which we hypothesized may interact with heparan sulfate proteoglycans. We found that a monomeric fragment of proIAPP (residues 1-30) bound both heparin and heparan sulfate affinity columns. Substitution of alanine residues for two basic residues in the N-terminal cleavage site abolished heparin and heparan sulfate binding activity. These data suggest that monomeric N-terminal human proIAPP contains a heparin-binding domain that is lost during normal processing of proIAPP. Although islet amyloid fibrils bind to heparin and heparan sulfate, it is unknown which residues in IAPP may be responsible for this interaction or whether nonfibrillar (monomeric) human IAPP also binds to heparin. Three basic residues in human IAPP (Lys1 , A r g 1 1 , and His1 8 ) could potentially contribute to this binding by interacting with negatively charged sulfate groups in heparin. We found heparin significantly enhanced fibril formation by IAPP 1-37 and 11-37, but not IAPP 12-37, suggesting that A r g 1 1 may be important in the ability of heparin to enhance IAPP fibril formation. Fibrils generated from IAPP 20-29 (which contains no basic residues) did not bind heparin, supporting the possibility that specific basic re…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/15100
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note: DOMAINS IN ISLET A M Y L O I D POLYPEPTIDE IMPORTANT IN FIBRIL FORMATION A N D TOXICITY by KIRILY P A R K B.Sc, The University of British Columbia, 1993 Hons., The University of Queensland, 1997 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF GRADUATE STUDIES (Department of Pathology and Laboratory Medicine) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA July 2003 © Kirily Park, 2003 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of VznUC^ The University of British Columbia Vancouver, Canada DE-6 (2/88) Abstract: Islet amyloid deposits are a characteristic pathologic lesion of the pancreas in type 2 diabetes and are composed primarily o f the islet beta cell peptide islet amyloid polypeptide (IAPP or amylin). Islet amyloid fibrils are toxic to insulin-producing beta cells. Heparan sulfate proteoglycans (HSPGs) are also a component of islet amyloid in vivo and accelerate amyloid fibril formation in vitro. Although the cause of amyloid formation in pancreatic islets is unknown, HSPGs have been proposed to play an initiating role. Impaired processing o f proIAPP, the I A P P precursor, has also been implicated in the mechanism of islet amyloid formation. The N - and C-terminal cleavage sites at which proIAPP is processed by prohormone convertases contain series of basic amino acid residues which we hypothesized may interact with heparan sulfate proteoglycans. We found that a mono…
has type: Thesis/Dissertation
date issued: 2003-11
is shown at: 10.14288/1.0091262
language: eng
degree discipline: Pathology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/15100