The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane
Open accessAbstract
Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulin-producing islet β cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this β cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.
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Cites
Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
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Self-citation
Cited by
Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus
Westermark, P., Andersson, A., & Westermark, G. T. (2011) · Physiological Reviews · doi:10.1152/physrev.00042.2009 · Cited by 1,044
Amyloidogenic Protein–Membrane Interactions: Mechanistic Insight from Model Systems
Butterfield, S. M., & Lashuel, H. A. (2010) · Angewandte Chemie International Edition · doi:10.1002/anie.200906670 · Cited by 592
The expanding amyloid family: Structure, stability, function, and pathogenesis
Sawaya, M. R., Hughes, M. P., Rodriguez, J. A., Riek, R., & Eisenberg, D. S. (2021) · Cell · doi:10.1016/j.cell.2021.08.013 · Cited by 475
Williams, T. L., & Serpell, L. C. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2011.08228.x · Cited by 335
Islet amyloid polypeptide: structure, function, and pathophysiology
Akter, R., Cao, P., Noor, H., Ridgway, Z., Tu, L.-H., Wang, H., Wong, A. G., Zhang, X., Abedini, A., Schmidt, A. M., et al. (2016) · Journal of Diabetes Research · doi:10.1155/2016/2798269 · Cited by 273
Metadata
- Authors
- Engel, M. F. M., Khemtémourian, L., Kleijer, C. C., Meeldijk, H. J. D., Jacobs, J., Verkleij, A. J., de Kruijff, B., Killian, J. A., & Höppener, J. W. M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2008-04-22
- Volume
- 105
- Issue
- 16
- Pages
- 6033-6038
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2141035467
- Cited by
- 466
- References
- 49
- FWCI
- 21.92
- Type
- journal article
- Language
- en
- Open access
- green
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- Engel, M. F. M., Khemtémourian, L., Kleijer, C. C., Meeldijk, H. J. D., Jacobs, J., Verkleij, A. J., de Kruijff, B., Killian, J. A., & Höppener, J. W. M. (2008). Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0708354105
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