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Title: Fibrillar dimer formation of islet amyloid polypeptides

Abstract

Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.

Authors:
 [1];  [1]
  1. Univ. of Chicago, IL (United States); Argonne National Lab. (ANL), Argonne, IL (United States)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Science Foundation (NSF); USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1247157
DOE Contract Number:  
AC02-06CH11357
Resource Type:
Journal Article
Journal Name:
AIP Advances
Additional Journal Information:
Journal Volume: 5; Journal Issue: 9; Journal ID: ISSN 2158-3226
Publisher:
American Institute of Physics (AIP)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Chiu, Chi-cheng, and de Pablo, Juan J. Fibrillar dimer formation of islet amyloid polypeptides. United States: N. p., 2015. Web. doi:10.1063/1.4921073.
Chiu, Chi-cheng, & de Pablo, Juan J. Fibrillar dimer formation of islet amyloid polypeptides. United States. https://doi.org/10.1063/1.4921073
Chiu, Chi-cheng, and de Pablo, Juan J. 2015. "Fibrillar dimer formation of islet amyloid polypeptides". United States. https://doi.org/10.1063/1.4921073.
@article{osti_1247157,
title = {Fibrillar dimer formation of islet amyloid polypeptides},
author = {Chiu, Chi-cheng and de Pablo, Juan J.},
abstractNote = {Amyloid deposits of human islet amyloid polypeptide (hIAPP), a 37-residue hormone co-produced with insulin, have been implicated in the development of type 2 diabetes. Residues 20 – 29 of hIAPP have been proposed to constitute the amyloidogenic core for the aggregation process, yet the segment is mostly unstructured in the mature fibril, according to solid-state NMR data. Here we use molecular simulations combined with bias-exchange metadynamics to characterize the conformational free energies of hIAPP fibrillar dimer and its derivative, pramlintide. We show that residues 20 – 29 are involved in an intermediate that exhibits transient β-sheets, consistent with recent experimental and simulation results. By comparing the aggregation of hIAPP and pramlintide, we illustrate the effects of proline residues on inhibition of the dimerization of IAPP. The mechanistic insights presented here could be useful for development of therapeutic inhibitors of hIAPP amyloid formation.},
doi = {10.1063/1.4921073},
url = {https://www.osti.gov/biblio/1247157}, journal = {AIP Advances},
issn = {2158-3226},
number = 9,
volume = 5,
place = {United States},
year = {Fri May 08 00:00:00 EDT 2015},
month = {Fri May 08 00:00:00 EDT 2015}
}

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Works referencing / citing this record:

Synergistic long-range effects of mutations underlie aggregation propensities of amylin analogues
journal, August 2019


Early-stage human islet amyloid polypeptide aggregation: Mechanisms behind dimer formation
journal, July 2018