The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide
Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-c...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmolb.2021.657946/full |
| _version_ | 1819086716928000000 |
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| author | Mikkel Christensen Mikkel Christensen Mikkel Christensen Nils A. Berglund Birgit Schiøtt Birgit Schiøtt |
| author_facet | Mikkel Christensen Mikkel Christensen Mikkel Christensen Nils A. Berglund Birgit Schiøtt Birgit Schiøtt |
| author_sort | Mikkel Christensen |
| collection | DOAJ |
| description | Islet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect. |
| first_indexed | 2024-12-21T21:24:41Z |
| format | Article |
| id | doaj.art-4d0e81fc59c54a07bd64be52dd95be0e |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-21T21:24:41Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-4d0e81fc59c54a07bd64be52dd95be0e2022-12-21T18:49:48ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2021-04-01810.3389/fmolb.2021.657946657946The Effect of Cholesterol on Membrane-Bound Islet Amyloid PolypeptideMikkel Christensen0Mikkel Christensen1Mikkel Christensen2Nils A. Berglund3Birgit Schiøtt4Birgit Schiøtt5Department of Chemistry, Aarhus University, Aarhus, DenmarkInterdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, DenmarkSino-Danish Center for Education and Research, Beijing, ChinaDepartment of Chemistry, Aarhus University, Aarhus, DenmarkDepartment of Chemistry, Aarhus University, Aarhus, DenmarkInterdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus, DenmarkIslet amyloid polypeptide (IAPP) is a proposed cause of the decreased beta-cell mass in patients with type-II diabetes. The molecular composition of the cell-membrane is important for regulating IAPP cytotoxicity and aggregation. Cholesterol is present at high concentrations in the pancreatic beta-cells, and in-vitro experiments have indicated that it affects the amyloid formation of IAPP either by direct interactions or by changing the properties of the membrane. In this study we apply atomistic, unbiased molecular dynamics simulations at a microsecond timescale to investigate the effect of cholesterol on membrane bound IAPP. Simulations were performed with various combinations of cholesterol, phosphatidylcholine (PC) and phosphatidylserine (PS) lipids. In all simulations, the helical structure of monomer IAPP was stabilized by the membrane. We found that cholesterol decreased the insertion depth of IAPP compared to pure phospholipid membranes, while PS lipids counteract the effect of cholesterol. The aggregation propensity has previously been proposed to correlate with the insertion depth of IAPP, which we found to decrease with the increased ordering of the lipids induced by cholesterol. Cholesterol is depleted in the vicinity of IAPP, and thus our results suggest that the effect of cholesterol is indirect.https://www.frontiersin.org/articles/10.3389/fmolb.2021.657946/fullcholesterolamylinsimulationsdiabetesaggregationamyloid |
| spellingShingle | Mikkel Christensen Mikkel Christensen Mikkel Christensen Nils A. Berglund Birgit Schiøtt Birgit Schiøtt The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide Frontiers in Molecular Biosciences cholesterol amylin simulations diabetes aggregation amyloid |
| title | The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide |
| title_full | The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide |
| title_fullStr | The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide |
| title_full_unstemmed | The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide |
| title_short | The Effect of Cholesterol on Membrane-Bound Islet Amyloid Polypeptide |
| title_sort | effect of cholesterol on membrane bound islet amyloid polypeptide |
| topic | cholesterol amylin simulations diabetes aggregation amyloid |
| url | https://www.frontiersin.org/articles/10.3389/fmolb.2021.657946/full |
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