Conserved and cooperative assembly of membrane-bound α-helical states of islet amyloid polypeptide
Conserved and cooperative assembly of membrane-bound α-helical states of islet amyloid polypeptide
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DOI：
10.1021/bi060579z
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发表时间：
2006-08-08
期刊：
影响因子：
2.9
通讯作者：
Miranker, Andrew D.
中科院分区：
文献类型：
--
作者：
Knight, Jefferson D.;Hebda, James A.;Miranker, Andrew D.
可溶性蛋白转化为富含-薄片的淀粉样蛋白纤维是许多严重疾病的标志。许多这些系统的前体（例如，来自阿尔茨海默病的A）与生物膜密切相关。据报道，膜双分子层可以加快淀粉样蛋白的组装速度。此外，淀粉样蛋白肽的膜通透性可导致毒性。考虑到成熟淀粉样蛋白富含β -薄片的性质，许多前体要么本质上是α -螺旋的，要么在与膜结合时短暂地采用α -螺旋状态，这似乎是矛盾的。在这项工作中，我们研究了这些现象在胰岛淀粉样蛋白多肽（IAPP）。IAPP是一种37残基肽激素，在II型糖尿病患者体内形成淀粉样蛋白纤维。尽管在膜上呈α -螺旋状态，但脂质双分子层明显加速了人IAPP （hIAPP）纤维的形成。我们进一步表明，IAPP分为单体和低聚螺旋组装。重要的是，正是后一种状态与膜渗漏和加速纤维形成最密切相关。来自啮齿类动物的IAPP序列变体（rIAPP）不形成纤维，并且被认为不会渗透膜。在这里，我们报道了在允许rIAPP膜结合的条件下，rIAPP能够渗透膜。rIAPP和hIAPP的序列和光谱比较使我们能够提出体外淀粉样蛋白螺旋加速形成的一般机制。由于rIAPP不能形成淀粉样纤维，我们的研究结果表明，纤维的形成不一定与毒性直接相关。
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.