[NMR paper] Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP.

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Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP.

Related Articles Cations as Switches of Amyloid-Mediated Membrane Disruption Mechanisms: Calcium and IAPP.

Biophys J. 2013 Jan 8;104(1):173-84

Authors: Sciacca MF, Milardi D, Messina GM, Marletta G, Brender JR, Ramamoorthy A, La Rosa C

Abstract
Disruption of the integrity of the plasma membrane by amyloidogenic proteins is linked to the pathogenesis of a number of common age-related diseases. Although accumulating evidence suggests that adverse environmental stressors such as unbalanced levels of metal ions may trigger amyloid-mediated membrane damage, many features of the molecular mechanisms underlying these events are unknown. Using human islet amyloid polypeptide (hIAPP, aka amylin), an amyloidogenic peptide associated with ?-cell death in type 2 diabetes, we demonstrate that the presence of Ca(2+) ions inhibits membrane damage occurring immediately after the interaction of freshly dissolved hIAPP with the membrane, but significantly enhances fiber-dependent membrane disruption. In particular, dye leakage, quartz crystal microbalance, atomic force microscopy, and NMR experiments show that Ca(2+) ions promote a shallow membrane insertion of hIAPP, which leads to the removal of lipids from the bilayer through a detergent-like mechanism triggered by fiber growth. Because both types of membrane-damage mechanisms are common to amyloid toxicity by most amyloidogenic proteins, it is likely that unregulated ion homeostasis, amyloid aggregation, and membrane disruption are all parts of a self-perpetuating cycle that fuels amyloid cytotoxicity.


PMID: 23332070 [PubMed - in process]



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