| Abstract
| - The conversion of soluble protein into β-sheet-rich amyloid fibers is the hallmark of a numberof serious diseases. Precursors for many of these systems (e.g., Aβ from Alzheimer's disease) reside inclose association with a biological membrane. Membrane bilayers are reported to accelerate the rate ofamyloid assembly. Furthermore, membrane permeabilization by amyloidogenic peptides can lead to toxicity.Given the β-sheet-rich nature of mature amyloid, it is seemingly paradoxical that many precursors areeither intrinsically α-helical or transiently adopt an α-helical state upon association with membrane. Inthis work, we investigate these phenomena in islet amyloid polypeptide (IAPP). IAPP is a 37-residuepeptide hormone which forms amyloid fibers in individuals with type II diabetes. Fiber formation byhuman IAPP (hIAPP) is markedly accelerated by lipid bilayers despite adopting an α-helical state on themembrane. We further show that IAPP partitions into monomeric and oligomeric helical assemblies.Importantly, it is this latter state which most strongly correlates to both membrane leakage and acceleratedfiber formation. A sequence variant of IAPP from rodents (rIAPP) does not form fibers and is reputed notto permeabilize membranes. Here, we report that rIAPP is capable of permeabilizing membranes underconditions that permit rIAPP membrane binding. Sequence and spectroscopic comparisons of rIAPP andhIAPP enable us to propose a general mechanism for the helical acceleration of amyloid formation invitro. As rIAPP cannot form amyloid fibers, our results show that fiber formation need not be directlycoupled to toxicity.
|
