Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines
The human Islet Amyloid Polypeptide (hIAPP) is the major constituent of amyloid deposits in pancreatic islets of type-II diabetes. IAPP is secreted together with insulin from the acidic secretory granules at a low pH of approximately 5.5 to the extracellular environment at a neutral pH. The increase...
| Main Authors: | , , , |
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| Format: | Journal Article |
| Language: | English |
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2013
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| Online Access: | https://hdl.handle.net/10356/98369 http://hdl.handle.net/10220/13354 |
| _version_ | 1811691797504589824 |
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| author | Li, Yang Xu, Weixin Mu, Yuguang Zhang, John Z. H. |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Li, Yang Xu, Weixin Mu, Yuguang Zhang, John Z. H. |
| author_sort | Li, Yang |
| collection | NTU |
| description | The human Islet Amyloid Polypeptide (hIAPP) is the major constituent of amyloid deposits in pancreatic islets of type-II diabetes. IAPP is secreted together with insulin from the acidic secretory granules at a low pH of approximately 5.5 to the extracellular environment at a neutral pH. The increased accumulation of extracellular hIAPP in diabetes indicates that changes in pH may promote amyloid formation. To gain insights and underlying mechanisms of the pH effect on hIAPP fibrillogenesis, all-atom molecular dynamics simulations in explicit solvent model were performed to study the structural properties of five hIAPP protofibrillar oligomers, under acidic and neutral pH, respectively. In consistent with experimental findings, simulation results show that acidic pH is not conducive to the structural stability of these oligomers. This provides a direct evidence for a recent experiment [L. Khemtemourian, E. Domenech, J. P. F. Doux, M. C. Koorengevel, and J. A. Killian, J. Am. Chem. Soc. 133, 15598 (2011)]10.1021/ja205007j, which suggests that acidic pH inhibits the fibril formation of hIAPP. In addition, a complementary coarse-grained simulation shows the repulsive electrostatic interactions among charged His18 residues slow down the dimerization process of hIAPP by twofold. Besides, our all-atom simulations reveal acidic pH mainly affects the local structure around residue His18 by destroying the surrounding hydrogen-bonding network, due to the repulsive interactions between protonated interchain His18 residues at acidic pH. It is also disclosed that the local interactions nearby His18 operating between adjacent β-strands trigger the structural transition, which gives hints to the experimental findings that the rate of hIAPP fibril formation and the morphologies of the fibrillar structures are strongly pH-dependent |
| first_indexed | 2024-10-01T06:25:36Z |
| format | Journal Article |
| id | ntu-10356/98369 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:25:36Z |
| publishDate | 2013 |
| record_format | dspace |
| spelling | ntu-10356/983692023-02-28T17:04:36Z Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines Li, Yang Xu, Weixin Mu, Yuguang Zhang, John Z. H. School of Biological Sciences DRNTU::Science::Biological sciences The human Islet Amyloid Polypeptide (hIAPP) is the major constituent of amyloid deposits in pancreatic islets of type-II diabetes. IAPP is secreted together with insulin from the acidic secretory granules at a low pH of approximately 5.5 to the extracellular environment at a neutral pH. The increased accumulation of extracellular hIAPP in diabetes indicates that changes in pH may promote amyloid formation. To gain insights and underlying mechanisms of the pH effect on hIAPP fibrillogenesis, all-atom molecular dynamics simulations in explicit solvent model were performed to study the structural properties of five hIAPP protofibrillar oligomers, under acidic and neutral pH, respectively. In consistent with experimental findings, simulation results show that acidic pH is not conducive to the structural stability of these oligomers. This provides a direct evidence for a recent experiment [L. Khemtemourian, E. Domenech, J. P. F. Doux, M. C. Koorengevel, and J. A. Killian, J. Am. Chem. Soc. 133, 15598 (2011)]10.1021/ja205007j, which suggests that acidic pH inhibits the fibril formation of hIAPP. In addition, a complementary coarse-grained simulation shows the repulsive electrostatic interactions among charged His18 residues slow down the dimerization process of hIAPP by twofold. Besides, our all-atom simulations reveal acidic pH mainly affects the local structure around residue His18 by destroying the surrounding hydrogen-bonding network, due to the repulsive interactions between protonated interchain His18 residues at acidic pH. It is also disclosed that the local interactions nearby His18 operating between adjacent β-strands trigger the structural transition, which gives hints to the experimental findings that the rate of hIAPP fibril formation and the morphologies of the fibrillar structures are strongly pH-dependent Published version 2013-09-06T02:54:07Z 2019-12-06T19:54:17Z 2013-09-06T02:54:07Z 2019-12-06T19:54:17Z 2013 2013 Journal Article Li, Y., Xu, W., Mu, Y., & Zhang, J. Z. H. (2013). Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines. The Journal of Chemical Physics, 139(5), 055102. 0021-9606 https://hdl.handle.net/10356/98369 http://hdl.handle.net/10220/13354 10.1063/1.4817000 en The journal of chemical physics © 2013 AIP Publishing LLC. This paper was published in The Journal of Chemical Physics and is made available as an electronic reprint (preprint) with permission of AIP Publishing LLC. The paper can be found at the following official DOI: [http://dx.doi.org/10.1063/1.4817000]. One print or electronic copy may be made for personal use only. Systematic or multiple reproduction, distribution to multiple locations via electronic or other means, duplication of any material in this paper for a fee or for commercial purposes, or modification of the content of the paper is prohibited and is subject to penalties under law. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences Li, Yang Xu, Weixin Mu, Yuguang Zhang, John Z. H. Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| title | Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| title_full | Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| title_fullStr | Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| title_full_unstemmed | Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| title_short | Acidic pH retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| title_sort | acidic ph retards the fibrillization of human islet amyloid polypeptide due to electrostatic repulsion of histidines |
| topic | DRNTU::Science::Biological sciences |
| url | https://hdl.handle.net/10356/98369 http://hdl.handle.net/10220/13354 |
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