Conserved and cooperative assembly of membrane-bound α-helical states of islet amyloid polypeptide

被引:268
作者
Knight, Jefferson D.
Hebda, James A.
Miranker, Andrew D.
机构
[1] Yale Univ, Dept Pharmacol, New Haven, CT 06520 USA
[2] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA
关键词
D O I
10.1021/bi060579z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The conversion of soluble protein into, beta-sheet-rich amyloid fibers is the hallmark of a number of serious diseases. Precursors for many of these systems (e. g., A, from Alzheimer's disease) reside in close association with a biological membrane. Membrane bilayers are reported to accelerate the rate of amyloid assembly. Furthermore, membrane permeabilization by amyloidogenic peptides can lead to toxicity. Given the, beta-sheet-rich nature of mature amyloid, it is seemingly paradoxical that many precursors are either intrinsically alpha-helical or transiently adopt an alpha-helical state upon association with membrane. In this work, we investigate these phenomena in islet amyloid polypeptide (IAPP). IAPP is a 37-residue peptide hormone which forms amyloid fibers in individuals with type II diabetes. Fiber formation by human IAPP (hIAPP) is markedly accelerated by lipid bilayers despite adopting an alpha-helical state on the membrane. 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 accelerated fiber formation. A sequence variant of IAPP from rodents (rIAPP) does not form fibers and is reputed not to permeabilize membranes. Here, we report that rIAPP is capable of permeabilizing membranes under conditions that permit rIAPP membrane binding. Sequence and spectroscopic comparisons of rIAPP and hIAPP enable us to propose a general mechanism for the helical acceleration of amyloid formation in vitro. As rIAPP cannot form amyloid fibers, our results show that fiber formation need not be directly coupled to toxicity.
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收藏
页码:9496 / 9508
页数:13
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