2012年9月3日 訊 /生物谷BIOON/ --近日,,來自田納西大學(xué)的分子生物學(xué)家發(fā)現(xiàn)了雙鏈RNA分子如何在細(xì)胞處于正常狀態(tài)和疾病狀態(tài)下被改造修飾,。相應(yīng)的研究成果刊登在了國(guó)際著名雜志Nature上,,該研究或許為治療人類某些癌癥和病毒感染提供幫助,。
在研究中,,研究者發(fā)現(xiàn),,在古老生命中的DEAD-box蛋白質(zhì)酶類或許可以像納米活塞(nanopistons)的重復(fù)利用一樣來發(fā)揮功能,,研究者使用化學(xué)能量來打開RNA鏈,,隨后建立新的結(jié)構(gòu),。研究者Lambowitz表示,在所有有機(jī)體的細(xì)胞中,,RNA在遺傳信息的翻譯和蛋白質(zhì)的合成上都扮演著重要的角色,,DEAD-box蛋白質(zhì)是我們所知的最大家族的RNA解鏈酶,其可以輕松打開RNA鏈,。在某些時(shí)候,,這些酶類并不行使傳統(tǒng)的解鏈酶的功能。
研究者假設(shè)DEAD-box蛋白質(zhì)可以在不同結(jié)構(gòu)域上發(fā)揮功能,,蛋白質(zhì)的一部分結(jié)合ATP分子,,提供能量;另外第二部分結(jié)合雙鏈RNA,。一旦第二個(gè)結(jié)構(gòu)域結(jié)合到了RNA上,,那么第一部分就會(huì)獲得ATP。
研究者在酵母Mss116p中揭示了這種機(jī)制,,而且這種機(jī)制通用于整個(gè)蛋白質(zhì)家族,。每一個(gè)DEAD-box蛋白質(zhì)都有著相同的結(jié)構(gòu),而且其使用相同的機(jī)制來發(fā)揮作用,。在酵母細(xì)胞中發(fā)現(xiàn)的DEAD-box蛋白質(zhì)可以識(shí)別雙鏈RNA,,其對(duì)于健康細(xì)胞發(fā)揮功能至關(guān)重要,。
在癌癥細(xì)胞中,其會(huì)被“劫持”,,高表達(dá)DEAD-box蛋白質(zhì)可以幫助控制失控的癌細(xì)胞增殖,,并且可以控制細(xì)菌、病毒或者真菌引發(fā)的感染,。后期研究者將深入研究為何DEAD-box蛋白質(zhì)以癌癥或者感染為靶點(diǎn)來發(fā)揮作用,。(生物谷Bioon.com)
編譯自:Ancient Enzymes Function Like Nanopistons to Unwind RNA
doi:10.1038/nature11402
PMC:
PMID:
Structural basis for RNA-duplex recognition and unwinding by the DEAD-box helicase Mss116p
Anna L. Mallam, Mark Del Campo, Benjamin Gilman, David J. Sidote & Alan M. Lambowitz
DEAD-box proteins are the largest family of nucleic acid helicases, and are crucial to RNA metabolism throughout all domains of life1, 2. They contain a conserved ‘helicase core’ of two RecA-like domains (domains (D)1 and D2), which uses ATP to catalyse the unwinding of short RNA duplexes by non-processive, local strand separation3. This mode of action differs from that of translocating helicases and allows DEAD-box proteins to remodel large RNAs and RNA–protein complexes without globally disrupting RNA structure4. However, the structural basis for this distinctive mode of RNA unwinding remains unclear. Here, structural, biochemical and genetic analyses of the yeast DEAD-box protein Mss116p indicate that the helicase core domains have modular functions that enable a novel mechanism for RNA-duplex recognition and unwinding. By investigating D1 and D2 individually and together, we find that D1 acts as an ATP-binding domain and D2 functions as an RNA-duplex recognition domain. D2 contains a nucleic-acid-binding pocket that is formed by conserved DEAD-box protein sequence motifs and accommodates A-form but not B-form duplexes, providing a basis for RNA substrate specificity. Upon a conformational change in which the two core domains join to form a ‘closed state’ with an ATPase active site, conserved motifs in D1 promote the unwinding of duplex substrates bound to D2 by excluding one RNA strand and bending the other. Our results provide a comprehensive structural model for how DEAD-box proteins recognize and unwind RNA duplexes. This model explains key features of DEAD-box protein function and affords a new perspective on how the evolutionarily related cores of other RNA and DNA helicases diverged to use different mechanisms