Structural insights into a zinc-dependent pathway leading to Leu55Pro transthyretin amyloid fibrils
Structural insights into a zinc-dependent pathway leading to Leu55Pro transthyretin amyloid fibrils
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DOI：
10.1107/s090744491104491x
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发表时间：
2011-12-01
影响因子：
2.2
通讯作者：
Damas, Ana M.
中科院分区：
文献类型：
--
作者：
Castro-Rodrigues, Artur F.;Gales, Luis;Damas, Ana M.
人转甲状腺素（TTR）是一种同四聚体蛋白，在常见淀粉样变性多发性神经病（FAP）、常见淀粉样变性心肌病（FAC）和老年性系统性淀粉样变性病（SSA）患者中负责淀粉样蛋白的形成。淀粉样蛋白原纤维具有交叉结构。然而，关于TTR单体如何组织形成这种组装体的细节仍然未知。Zn2+增加TTR L55P淀粉样变性的作用已有报道。TTR L55P-Zn2+配合物的晶体生长条件与变异蛋白淀粉样变电位较高的条件相似，并通过x射线晶体学确定了配合物的三维结构。确定了两个不同的四面体Zn2+结合位点：一个交联两个四聚体，而另一个位于二聚体中两个单体之间的界面。涉及两个Zn2+结合位点的单体结合导致具有交叉结构的二维阵列。这种结构的形成和随后的组织成淀粉样原纤维是由荧光光谱和电子显微镜监测。TTR L55P-Zn2+结构提供了Zn2+在TTR淀粉样变性中作为交叉β型结构介质的作用的第一个分子见解，并讨论了导致早期淀粉样变性中间体产生的Zn2+依赖途径的相关性。
Human transthyretin (TTR) is a homotetrameric protein that is responsible for the formation of amyloid in patients with familiar amyloidotic polyneuropathy (FAP), familiar amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA). Amyloid fibrils are characterized by a cross-beta structure. However, details of how TTR monomers are organized to form such an assembly remain unknown. The effect of Zn2+ in increasing TTR L55P amyloidogenecity has been reported. Crystals of the TTR L55P-Zn2+ complex were grown under conditions similar to those leading to higher amyloidogenic potential of the variant protein and the three-dimensional structure of the complex was determined by X-ray crystallography. Two different tetrahedral Zn2+-binding sites were identified: one cross-links two tetramers, while the other lies at the interface between two monomers in a dimer. The association of monomers involving the two Zn2+-binding sites leads to a bidimensional array with a cross-beta structure. The formation of this structure and subsequent organization into amyloid fibrils was monitored by fluorescence spectroscopy and electron microscopy. The TTR L55P-Zn2+ structure offers the first molecular insights into the role of Zn2+ as a mediator of cross-beta-type structure in TTR amyloidosis and the relevance of a Zn2+-dependent pathway leading to the production of early amyloidogenic intermediates is discussed.