Triggers of full-length tau aggregation: A role for partially folded interrnediates
Triggers of full-length tau aggregation: A role for partially folded interrnediates
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DOI：
10.1021/bi0500123
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发表时间：
2005-04-19
期刊：
影响因子：
2.9
通讯作者：
Kuret, J
中科院分区：
文献类型：
--
作者：
Chirita, CN;Congdon, EE;Kuret, J
阿尔茨海默病的部分特征在于全长tau蛋白积累到细胞内丝状包涵体中。为了阐明触发病变形成的事件，重组全长四重复tau（htau 40）的聚集在体外检查在接近生理条件下，使用透射电子显微镜和光谱学方法。在没有外源诱导物的情况下，tau蛋白表现为具有很少三级结构的组装不合格单体。阴离子诱导剂的加入导致成核依赖动力学的纤维化。的圆二色光谱和与硫磺素S和8-苯胺基-1-萘磺酸荧光探针的反应性的基础上，诱导剂稳定的单体物种的折叠特性的预熔融球状态。能够以高亲和力结合中间态的平面芳香族染料也能够在不存在其他诱导剂的情况下触发氟化。染料介导的聚集的特征在于浓度依赖性的滞后时间的减少，表明增加的成核速率，和亚微摩尔临界浓度，表明最终的平衡，有利于丝状状态。数据表明，全长tau形成细丝的限速障碍是构象障碍，并且聚集反应是由稳定组装能力构象的环境条件触发的。
Alzheimer's disease is characterized in part by the accumulation of full-length tau proteins into intracellular filamentous inclusions. To clarify the events that trigger lesion formation, the aggregation of recombinant full-length four-repeat tau (htau40) was examined in vitro under near-physiological conditions using transmission electron microscopy and spectroscopy methods. In the absence of exogenous inducers, tau protein behaved as an assembly-incompetent monomer with little tertiary structure. The addition of anionic inducers led to fibrillization with nucleation-dependent kinetics. On the basis of circular dichroism spectroscopy and reactivity with thioflavin S and 8-anilino-1-naphthalenesulfonic acid fluorescent probes, the inducer stabilized a monomeric species with the folding characteristics of a premolten globule state. Planar aromatic dyes capable of binding the intermediate state with high affinity were also capable of triggering fibrillization in the absence of other inducers. Dye-mediated aggregation was characterized by concentration-dependent decreases in lag time, indicating increased nucleation rates, and submicromolar critical concentrations, indicating a final equilibrium that favored the filamentous state. The data suggest that the rate-limiting barrier for filament formation from full-length tau is conformational and that the aggregation reaction is triggered by environmental conditions that stabilize assembly-competent conformations.