组蛋白伴侣的鉴定与结构研究

真核生物的遗传信息存储在染色质中，染色质是由基本单位核小体经过多层次的压缩形成的一种高级结构。该结构可以有效地保护基因组的稳定性和完整性，有利于遗传信息的传递并保护其免受外界因素的破坏。为了保持染色质结构的完整性，需要对DNA复制、修复和基因转录等过程进行精细调控，这些过程伴随着核小体的组装、去组装和重新组装。作为核小体的核心成分，组蛋白在其伴侣的协助下完成多种代谢过程，维持核小体组装与去组装的动态平衡。因此，组蛋白伴侣是核小体和染色质结构动态调控的关键因素。目前，已知的组蛋白伴侣均来自于真核生物自身编码的蛋白质。虽然已经进行了大量研究，但仍需要进一步探究是否存在新的组蛋白伴侣以及它们的调控方式。已知某些病毒（例如EB病毒）编码的蛋白质可以与宿主细胞的染色质结合，并结合组蛋白。然而，病毒编码的蛋白质是否具有组蛋白伴侣功能以及其具体的分子机制仍需进一步揭示。

EB病毒是最常见的侵染人类的病毒之一，与多种疾病和恶性肿瘤相关。该病毒编码的间质蛋白BKRF4可以与宿主细胞的组蛋白结合。为了验证其是否具有组蛋白分子伴侣的活性，我们进行了质粒超螺旋实验和核小体组装实验，结果显示BKRF4是一种来自EBV的组蛋白伴侣。为了进一步揭示BKRF4的作用机制，我们利用晶体学的方法解析了BKRF4 HBD-H3–H4-ASF1B四元复合物的结构，以及BKRF4 HBD-H2A–H2B三元复合物的结构。结构和生化分析的结果表明，组蛋白伴侣BKRF4主要利用保守序列“EIDL”结合H3–H4。基于“EIDL”和MCM2识别组蛋白H3–H4的序列“DGEEL”之间的相似性，我们提出保守基序D/EL是一种新的结合H3–H4的基序。此外，我们发现BKRF4通过保守序列“DPSWHP”与H2A–H2B结合，在该序列中，保守的天冬氨酸(D)和色氨酸(W)分别作为酸性螺旋帽和芳香锚定残基，这与其他已知的H2A–H2B伴侣利用苯丙氨酸(F)或酪氨酸(Y)作为芳香锚有所不同。因此，我们的工作将组蛋白伴侣识别H2A–H2B的结合基序拓展为DEF/Y/W基序。此外，我们的研究还发现BKRF4可以作为组蛋白八聚体的伴侣，并提出了它调节核小体组装的模型。上述实验结果证明BKRF4是一种典型的非真核生物编码的组蛋白伴侣。

在复制叉处，组蛋白伴侣FACT和DNA聚合酶pol a和e可能利用与BKRF4识别组蛋白的相似序列来参与亲本组蛋白的回收，我们对它们识别组蛋白的结构基础进行了探究。我们首先聚焦在可能参与亲本组蛋白回收的人源组蛋白伴侣FACT复合物上。该复合物由Spt16和SSRP1组成，是一种多功能组蛋白伴侣，它可以结合H2A–H2B二聚体、H3–H4四聚体（或二聚体）以及部分解开的核小体，但是缺乏阐释人源Spt16的羧基末端(hSpt16 CTD)如何识别组蛋白H2A–H2B二聚体的结构信息。结构和生化研究发现，hSpt16-CTD利用保守序列“DETFNP”结合H2A–H2B，该序列是DEF/Y/W基序。基序下游的保守脯氨酸残基充当辅助锚，增强其对组蛋白H2A–H2B的结合，这与BKRF4结合H2A–H2B的结构基础相一致。hSpt16-CTD-H2A–H2B结构解释了在复制叉处FACT识别H2A–H2B的机制。在此基础上，我们对复制叉处的亲本组蛋白H3–H4的回收机制进行了初步探究，即亲本组蛋白被DNA聚合酶a和e的亚基POLA1与POLE3回收的结构基础。我们目前解析出的人源POLA1-H3–H4和POLE3-H3–H4的低分辨率初始结构模型，提示POLA1和POLE3也可能是利用保守的D/EL基序识别H3–H4。

综上所述，本论文首次解析了EBV编码的间质蛋白质BKRF4与组蛋白复合物的晶体结构，证明了BKRF4是一个组蛋白伴侣，揭示了非真核生物编码的第一个组蛋白伴侣。基于我们利用晶体学方法解析的BKRF4 HBD-H3–H4-ASF1B四元复合物的结构、BKRF4 HBD-H2A–H2B三元复合物的结构和hSpt16-CTD-H2A–H2B三元复合物的结构，以及氨基酸序列分析，我们提出了组蛋白伴侣靶向H3–H4的全新保守基序D/EL基序，拓展了组蛋白伴侣识别H2A–H2B的保守基序为DEF/Y/W基序以及下游的脯氨酸残基为辅助锚，揭示了组蛋白伴侣识别组蛋白的共性。同时，我们也初步研究了亲本组蛋白被伴侣POLA1、POLE3回收的结构机理。我们的研究为组蛋白伴侣以及表观遗传研究领域提供了有价值的参考和启示。

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