这项研究打破细胞 - 结构生物学边界,看见“渐冻人”细胞内病变的结构基础

2018-04-13 寒雨 科研圈

低复杂度蛋白质聚集是神经退行性病变的重要标志。现在,一份此种聚集的高分辨率结构快照史无前例地呈现在我们面前,揭示出这些蛋白质对重要细胞功能的破坏。

低复杂度蛋白质聚集是神经退行性病变的重要标志。现在,一份此种聚集的高分辨率结构快照史无前例地呈现在我们面前,揭示出这些蛋白质对重要细胞功能的破坏。

神经退行性疾病常常与短核苷酸重复序列插入的基因突变有关。在肌萎缩性脊髓侧索硬化症(ALS,亦称运动神经元病、渐冻症)和额颞叶痴呆中,C9orf72 基因非编码区的短重复序列插入会产生含有甘氨酸(G)和丙氨酸(A)残基重复序列的异常翻译产物。这些 poly-GA 产物在神经元中形成聚集。既有研究显示,这些聚集会阻碍蛋白酶体复合物降解蛋白质这一关键细胞活动。然而,对于这种破坏产生的生化基础及其致病机制,我们仍然知之甚少。在这篇 Cell 文章中,郭强等人利用 3D 冷冻电子断层扫描技术(cryo-ET)精确地绘制了神经元中 poly-GA 聚集和相关大分子复合物的组织和结构特征,将 poly-GA 对蛋白酶体的破坏直观地展现出来。

3D cryo-ET 使用电子显微镜从不同角度对一个超薄、冷冻、含水的细胞切片进行观察,并由此重构出三维立体图像。作者利用 3D cryo-ET 实现了神经元的可视化,这些神经元经过遗传改造,表达包含 175 个或 73 个拷贝的 poly-GA 片段。这些片段带有绿色荧光蛋白标签,可以被光学显微镜精确定位。在体内,C9orf72 扩增需要很长时间来形成 poly-GA 片段,而这些工程蛋白可以有效地对内源 poly-GA 片段进行模拟。作者发现,poly-GA 蛋白呈高度簇状,由厚度相对均匀,但长度和宽度存在差异的纽带结构组成并时常具有二叉状分支结构,这一结果与先前常规电子显微镜的体外观察结果相似。

这项工作不仅观察了细胞中 poly-GA 聚集的详细结构,而且将 poly-GA 结构与 poly- Q 结构进行了比较。Poly- Q 是另一种基因异常扩增形成的聚集,可导致另一种神经退行性疾病:亨廷顿病。2016 年,该研究组已经完成了对其结构的 3D cryo-ET 分析。这种比较揭示出的结构差异,可以帮助研究者对两种聚集致病机制的差异进行解读

首先,两种聚集本身的结构是不同的。poly- Q 形成纤维状聚集,与 poly-GA 聚集相比,它很少分支,致密程度也更低。

其次,当作者使用计算手段,在聚集中搜寻已知的大分子复合物时,他们发现许多蛋白酶体被募集到了 poly-GA 聚集中(图 1)。而生化数据也表明,神经元中多达 50% 的蛋白酶体复合物都被募集于 poly-GA 纽带结构中。将蛋白酶体通过这种隔离机制从其在细胞中的正常位置移除,或许可以解释含有聚集的细胞中蛋白酶体活性的降低。核糖体是介导蛋白质合成的复合物,其大小与蛋白酶体相当,但极少存在于 polyGA 聚集物中,这表明蛋白酶体会主动招募 poly-GA 聚集或主动保持与 poly-GA 聚集的结合。poly- Q 纤维却与之不同,它不含蛋白酶体,但与多种细胞器的膜结构紧密接触,这种相互作用可以导致内质网等细胞器的膜结构发生形变。这种形变则可能影响蛋白质的翻译、运输和降解途径。



图 1 聚集毒性产生机制的对比。a, 与一大类 ALS 相关的 poly-GA 在神经元中形成聚集。作者 5 通过细胞内高分辨率结构,展示了与蛋白酶体(图中为蓝色)结合的由 poly-GA 形成的带状聚集(图中为红色)。蛋白酶体参与其他蛋白质的降解过程,它被 poly-GA 聚集捕获并处于功能停滞状态,从而导致细胞毒性。Poly-GA 聚集不与囊泡和内质网等具膜细胞器结合。b, 但与亨廷顿病相关的 poly- Q 聚集呈纤维状(图中为紫色)7,这些聚集使囊泡膜和内质网膜产生形变。这些结果表明不同的聚集可以通过不同的机制引起神经退行性改变。

蛋白酶体由桶状的核心亚基(蛋白质底物的切割降解在此发生)和一个或两个调节亚基组成,这些调节亚基覆盖在桶的末端,形成其盖子,对试图进入蛋白酶体内部的分子进行限制,保证只有携带泛素标记的蛋白才能进入。在既有研究中,研究者曾观察到调节颗粒的多种构象,表明蛋白酶体会在基态、准备态和底物结合态之间发生循环性的构象变化。作者使用计算方法对蛋白酶体图像进行平均,从而判断图像中蛋白酶体的状态,发现在 poly-GA 聚集内同时存在基态和底物结合态的蛋白酶体。他们还发现,与不含 poly-GA 产物的对照组神经元相比,表达 poly-GA 的神经元中具有两个调节亚基的蛋白酶体的比例大幅增加。聚集中接近四分之一的蛋白酶体都与一种近期解析的蛋白酶体构象一致,在这种构象下,蛋白酶体与底物结合,但底物被困于蛋白酶体核心亚基中,使蛋白酶体的功能处于阻滞状态。而在那些与 poly-GA 纽带最为接近的蛋白酶体中,处于阻滞状态的蛋白酶体比例更高,达到 36%。

为什么会发生这种阻滞?在重建的断层图像中,作者在 poly-GA 纽带和蛋白质 RAD23 与蛋白酶体的结合位点之间发现了许多有电子密度分布的区域。 RAD23 参与将泛素标记的蛋白底物募集到蛋白酶体的过程,并且会在 poly-GA 聚集中富集。由此推断,这些电子密度可能代表着与聚集内 RAD23 结合的泛素化标记的蛋白底物。研究者尚不清楚“噎住”蛋白酶体的究竟是哪些蛋白,但 poly-GA 片段本身很可能就是其中之一,并通过这种途径直接导致了蛋白酶体活性的降低。不管具体机制如何,细胞内蛋白酶体活性的降低都会对蛋白质降解途径有害,并由此导致细胞毒性。

这些结果又引出了几个需要回答的重要问题。

首先,由 C9orf72 扩增诱发的 ALS 被认为与 poly-GA 聚集形成以及 C9orf72 蛋白产物的减少都有关系,但这两种机制所造成的影响各有多大?C9orf72 蛋白参与形成细胞自噬相关的复合物 12。细胞自噬是细胞内蛋白质等组分被降解和循环利用的过程。因此,C9orf72 蛋白水平的降低可能与 poly-GA 依赖的蛋白酶体抑制共同增加了神经元毒性。

其次,poly-GA 聚集对其他蛋白质的捕获是否也会增加细胞毒性?在 poly-GA 聚集中富集的自噬相关蛋白 p62 就是进一步的研究对象之一。

第三,与聚集解聚相关的几种分子机器都没有在 poly-GA 结构中富集,其原因尚不清楚。

最后,poly-GA 是由 C9orf72 扩增产生的表达量最高的重复序列蛋白,但不是唯一一种——突变也可以产生甘氨酸 - 精氨酸(poly-GR)和脯氨酸 - 精氨酸(poly-PR)聚集。这些其他聚集的结构与 poly-GA 相比如何?大多数关于 poly-GR 和 poly-PR 聚集的既有数据认为它们不会缠结蛋白酶体,这意味着它们通过其他机制产生毒性。

进一步的 3D cryo-ET 研究,以及对于 C9orf72 插入突变序列的天然翻译产物,而非本研究中使用的构建蛋白产物进行深入分析,可能会澄清患者体内聚集与研究中使用的模型聚集之间的异同。

概括而言,此项工作以前所未有的分辨率,使用 3D cryo-ET 实现了对细胞内基本进程的可视化观测。此外,它为理解聚集相关神经退行性疾病的复杂机制奠定了新的基础。

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    0

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    2018-04-14 yfjms

    学习

    0

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    2018-04-13 坚强007

    高大上.学习中

    0

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    2018-04-13 惠映实验室

    学习了.谢谢分享.

    0

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