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施一公在《科学》同一期发表两篇论文，这是第二次！

2016-07-22 MedSci MedSci原创

施一公论文
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2016年7月22日，生命科学联合中心施一公研究组于《科学》（Science）杂志就剪接体的结构与机理研究发表两篇长文（Research Article），题目分别为《酵母剪接体激活状态3.5埃的结构》（Structure of a Yeast Activated Spliceosome at 3.5 A Resolution）和《第一步催化反应后的酵母剪接体3.4埃的结构》（Struct

大牛施一公 刚发1篇Nature 又来2篇Science
2016年7月22日，生命科学联合中心施一公研究组于《科学》（Science）杂志就剪接体的结构与机理研究发表两篇长文（Research Article），题目分别为《酵母剪接体激活状态3.5埃的结构》（Structure of a Yeast Activated Spliceosome at 3.5 A Resolution）和《第一步催化反应后的酵母剪接体3.4埃的结构》（Structure of a Yeast Catalytic Step I Spliceosome at 3.4 A Resolution），报道了酿酒酵母（Saccharomyces cerevisiae）剪接体激活和剪接反应催化过程中两个重要状态的剪接体复合物近原子分辨率的三维结构，阐明了剪接体的激活和催化机制，从而进一步揭示了前体信使RNA剪接反应（pre-mRNA splicing，以下简称RNA剪接）的分子机理。

RNA剪接是真核生物从DNA到蛋白质信息传递中心法则的关键一环。其主要执行者是一个极其复杂的分子机器——剪接体。通过剪接反应，前体信使RNA中数量、长度不等的内含子被剔除，剩下的外显子按照特异顺序连接起来从而形成成熟的信使RNA（mRNA），进一步在核糖体的催化下被翻译成蛋白质。RNA剪接的化学本质就是前体信使RNA经历两步转酯反应完成剪和接在两个关键步骤，而每一步都需要由剪接体催化完成。

剪接体是一个由大量蛋白因子介导、核酸（RNA）催化的金属核酶（protein-directed metalloribozyme）。在剪接反应过程中，组成剪接体的蛋白质-核酸复合物及剪接因子按照高度精确的顺序进行结合和解聚，并伴随大规模的结构重组，组装成一系列具有不同组分和构象的统称为剪接体的分子机器，根据它们在RNA剪接过程中的生化性质，这些剪接体又被人为区分为B、Bact、B*、C、P、ILS等若干状态。获取剪接体在激活及催化反应过程中不同状态的结构是最基础也是最富挑战性的结构生物学难题之一。2015年8月，施一公研究组率先突破，在世界上首次报道了裂殖酵母剪接体处于ILS状态的3.6埃高分辨率结构。

在最新发表的两篇《科学》论文中，施一公研究组进一步探索并优化了蛋白提纯方案，捕获了性质良好的酿酒酵母剪接体分别处于激活状态（activated spliceosome，又称为Bact complex）和第一步催化反应后（catalytic step I spliceosome，又称为C complex）的优质样品，并利用单颗粒冷冻电镜技术和高效的数据分类方法，重构出了总体分辨率分别为3.5和3.4埃的两个高分辨率冷冻电镜结构，并搭建了原子模型（图1，2）。这两个复合物近原子分辨率三维结构的解析，首次完整地展示了第一步转酯反应前后pre-mRNA和起催化作用的snRNA的反应状态，以及剪接体内部蛋白组分的组装情况。尤为值得一提的是，催化核心区域的分辨率达到了2.8至3.0埃，清晰的展示出剪接反应中心的结构信息，为解释剪接体对pre-mRNA splicing的催化机制提供了迄今最为清晰的关键证据。

如上两个结构与该研究组之前报道的ILS剪接体及2016年1月报道的3.8埃的酿酒酵母tri-snRNP结构的对比更为深刻的揭示了剪接体在pre-mRNA剪接反应过程中作为核酶催化完成两步转酯反应的本质，是RNA剪接研究领域的又一突破性进展。

清华大学医学院三年级博士生万蕊雪、生命学院博士后闫创业、生命学院一年级博士生白蕊为两篇文章的共同第一作者；生命学院一年级博士黄高兴宇为第二篇文章的共同第一作者；施一公为通讯作者。电镜数据采集于清华大学冷冻电镜平台，计算工作得到清华大学高性能计算平台、国家蛋白质设施实验技术中心(北京)、联想高性能计算、以及荣之联董事长王东辉先生的支持。本工作获得了北京结构生物学高精尖创新中心及国家自然科学基金委的经费支持。
图1 Bact complex电镜密度及三维结构示意图
图2 C complex电镜密度及三维结构示意图
图3 剪接反应机理图解

实际上，2015年8 月 21 日，他的研究组在《科学》（Science）上同时在线发表了两篇研究长文报道剪接体的三维结构并阐述 RNA 剪接的分子结构基础。题目分别为“3.6埃的酵母剪接 体结构”（Structure of a Yeast Spliceosome at 3.6 Angstrom Resolution）和“前体信使 RNA剪接的结构基础”（Structural Basis of Pre-mRNA Splicing）。

2015年8 月 18 日，该团队还在《自然》在线发表了题为《人源γ- 分泌酶的原子分辨率结构》的文章，为理解老年痴呆症发病机理提供重要基础。论文发表后，施一公表示：「这项研究成果的意义很可能超过了我过去 25 年科研生涯中所有研究成果的总和。」

在2016年1月，又发表了U4/U6.U5 tri-snRNP的3.8埃结构，文章在Science上。

哎，都成为Science专业户了。

原始出处：

Chuangye Yan*, Ruixue Wan*, Rui Bai*, Gaoxingyu Huang, Yigong Shi. Structure of a yeast catalytically activated spliceosome at 3.5 Å resolution.Science 21 Jul 2016: DOI: 10.1126/science.aag0291

Ruixue Wan*, Chuangye Yan*, Rui Bai*, Gaoxingyu Huang*, Yigong Shi.Structure of a yeast catalytic step I spliceosome at 3.4 Å resolution.Science 21 Jul 2016: DOI: 10.1126/science.aag2235

Wan R, Yan C, Bai R, Wang L, Huang M, Wong CC, Shi Y. The 3.8 Å structure of the U4/U6.U5 tri-snRNP: Insights into spliceosome assembly and catalysis. Science. 2016 Jan 29;351(6272):466-75.

Yan C, Hang J, Wan R, Huang M, Wong CC, Shi Y. Structure of a yeast spliceosome at 3.6-angstrom resolution. Science. 2015 Sep 11;349(6253):1182-91.

Hang J, Wan R, Yan C, Shi Y. Structural basis of pre-mRNA splicing. Science. 2015 Sep 11;349(6253):1191-8

Bai XC, Yan C, Yang G, Lu P, Ma D, Sun L, Zhou R, Scheres SH, Shi Y. An atomic structure of human γ-secretase. Nature. 2015 Sep 10;525(7568):212-7.

Yan Z, Bai XC, Yan C, Wu J, Li Z, Xie T, Peng W, Yin CC, Li X, Scheres SH, Shi Y, Yan N. Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution. Nature. 2015 Jan 1;517(7532):50-5.

Lu P, Bai XC, Ma D, Xie T, Yan C, Sun L, Yang G, Zhao Y, Zhou R, Scheres SH, Shi Y. Three-dimensional structure of human γ-secretase. Nature. 2014 Aug 14;512(7513):166-70.

Zhou L, Hang J, Zhou Y, Wan R, Lu G, Yin P, Yan C, Shi Y. Crystal structures of the Lsm complex bound to the 3' end sequence of U6 small nuclear RNA. Nature. 2014 Feb 6;506(7486):116-20

Yin P, Li Q, Yan C, Liu Y, Liu J, Yu F, Wang Z, Long J, He J, Wang HW, Wang J, Zhu JK, Shi Y, Yan N. Structural basis for the modular recognition of single-stranded RNA by PPR proteins. Nature. 2013 Dec 5;504(7478):168-71

Wang T, Fu G, Pan X, Wu J, Gong X, Wang J, Shi Y. Structure of a bacterial energy-coupling factor transporter. Nature. 2013 May 9;497(7448):272-6.

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    2016-07-23 doctorJiangchao

    值得收藏

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    2016-07-23 doctorJiangchao

    感谢平台

    0

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    2016-07-23 doctorJiangchao

    继续关注

    0

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    2016-07-23 oo902

    好好学习

    0

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    2016-07-23 lovetcm

    最关键技术是冷冻电镜，3.4埃，几乎是极限了

    0

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    2016-07-23 flyingzyx

    厉害！

    0

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    2016-07-23 zhyx

    同意3，4楼的观点，研究蛋白结构的文章这么容易上Science？！都这么有突破性？！怀疑！感觉好像什么地方有点“滥”？！

    0

  8. [GetPortalCommentsPageByObjectIdResponse(id=94396, encodeId=3403943964a, content=值得收藏, beContent=null, objectType=article, channel=null, level=null, likeNumber=83, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sat Jul 23 19:44:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94395, encodeId=11a894395e5, content=感谢平台, beContent=null, objectType=article, channel=null, level=null, likeNumber=99, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sat Jul 23 19:07:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94394, encodeId=5bc99439474, content=继续关注, beContent=null, objectType=article, channel=null, level=null, likeNumber=86, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sat Jul 23 19:06:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94247, encodeId=779f9424ec9, content=好好学习, beContent=null, objectType=article, channel=null, level=null, likeNumber=96, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=a37a1710612, createdName=oo902, createdTime=Sat Jul 23 11:23:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94215, encodeId=449c94215f7, content=最关键技术是冷冻电镜，3.4埃，几乎是极限了, beContent=null, objectType=article, channel=null, level=null, likeNumber=101, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c4a5105539, createdName=lovetcm, createdTime=Sat Jul 23 07:40:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94213, encodeId=996e9421373, content=厉害！, beContent=null, objectType=article, channel=null, level=null, likeNumber=50, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NcXNhUvfhzd2SEXGDldsNfP4rKvY7vJmaHcyvLXicuyaCTJtVOkX3jvd6DwNMD88hDjJwsU7MnUH6zeqC4zt3yGV/0, createdBy=4e701628585, createdName=flyingzyx, createdTime=Sat Jul 23 06:22:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94208, encodeId=15489420875, content=同意3，4楼的观点，研究蛋白结构的文章这么容易上Science？！都这么有突破性？！怀疑！感觉好像什么地方有点“滥”？！, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d12d104257, createdName=zhyx, createdTime=Sat Jul 23 00:40:00 CST 2016, time=2016-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94204, encodeId=2ec594204d7, content=望尘莫及！, beContent=null, objectType=article, channel=null, level=null, likeNumber=38, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=/v1.0.0/img/user_icon.png, createdBy=d0921674448, createdName=gyczyxy, createdTime=Fri Jul 22 23:44:00 CST 2016, time=2016-07-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94200, encodeId=ea809420045, content=牛人！, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=93f31631454, createdName=1dd8c52fm63(暂无匿称), createdTime=Fri Jul 22 22:54:00 CST 2016, time=2016-07-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=94190, encodeId=78ca94190bb, content=严重抗议这样灌水！一年好多篇，别人咋办?, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=c4a5105539, createdName=lovetcm, createdTime=Fri Jul 22 20:51:00 CST 2016, time=2016-07-22, status=1, ipAttribution=)]
    2016-07-22 gyczyxy

    望尘莫及！

    0

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    2016-07-22 1dd8c52fm63(暂无匿称)

    牛人！

    0

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    2016-07-22 lovetcm

    严重抗议这样灌水！一年好多篇，别人咋办?

    0

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