近日，國(guó)際著名雜志《細(xì)胞》子刊《結(jié)構(gòu)》（Structure）報(bào)道了中科院上海生科院生化與細(xì)胞所丁建平組,、周金秋組關(guān)于MHF復(fù)合物的最新研究成果,。
范可尼貧血癥（Fanconi anemia，F(xiàn)A）是一種遺傳性血液系統(tǒng)疾病,，患者除骨髓造血功能障礙導(dǎo)致全血細(xì)胞減少外,，還伴有多發(fā)性先天畸形，并易患多種癌癥。范可尼貧血癥特征之一為細(xì)胞染色體的不穩(wěn)定性,，已有研究結(jié)果表明,，直接參與DNA損傷修復(fù)過(guò)程的13個(gè)FANC蛋白和兩個(gè)FAAP蛋白與FA的發(fā)生相關(guān)。最近新發(fā)現(xiàn)兩個(gè)蛋白MHF1和MHF2所形成的復(fù)合物能促進(jìn)FANCM對(duì)DNA的結(jié)合,，MHF復(fù)合物,、FANCM以及DNA的結(jié)合為下游FANCD2發(fā)揮功能，繼而完成DNA鏈內(nèi)交聯(lián)損傷修復(fù)所必需,。此外,，研究表明MHF復(fù)合物在動(dòng)粒組裝過(guò)程中也發(fā)揮十分重要的作用。
丁建平組博士生楊薈等人解析了酵母源MHF復(fù)合物的晶體結(jié)構(gòu),。結(jié)構(gòu)分析和生化數(shù)據(jù)表明,，MHF1和MHF2都呈現(xiàn)出經(jīng)典的組蛋白折疊（histone fold）結(jié)構(gòu)，MHF1和MHF2形成1：1的異源四聚體,，四聚體的結(jié)構(gòu)與組蛋白(H3-H4)2結(jié)構(gòu)非常相似,。通過(guò)結(jié)構(gòu)比較和序列保守性分析，發(fā)現(xiàn)MHF1的L2環(huán)區(qū)氨基酸序列在各物種中比較保守,，并且這一區(qū)域的結(jié)構(gòu)與H3的相應(yīng)結(jié)構(gòu)在氨基酸組成,、側(cè)鏈走向和整體構(gòu)象上都非常相似，提示該區(qū)域的功能可能與H3中相應(yīng)區(qū)域類(lèi)似,，也參與DNA的結(jié)合,。MHF復(fù)合物中含有兩個(gè)MHF1-MHF2異源二聚體，通過(guò)其中兩個(gè)MHF1分子的a螺旋a2,、a3和環(huán)區(qū)L3相互作用,，組裝成異源四聚體；異源四聚體界面上參與親水和疏水相互作用的氨基酸都十分保守,。
進(jìn)一步的生化數(shù)據(jù)和突變體酵母表型分析結(jié)果顯示,，MHF復(fù)合物四聚體的形成對(duì)其在DNA修復(fù)過(guò)程中的生物學(xué)功能至關(guān)重要。
這一研究成果將有助于人們進(jìn)一步理解MHF復(fù)合物發(fā)揮DNA修復(fù)功能的分子機(jī)制,。
該項(xiàng)工作得到科技部,、國(guó)家自然科學(xué)基金委、中國(guó)科學(xué)院和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi:10.1016/j.str.2011.12.012
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Saccharomyces Cerevisiae MHF Complex Structurally Resembles the Histones (H3-H4)2 Heterotetramer and Functions as a Heterotetramer
Hui Yang1, 2, Tianlong Zhang1, Ye Tao1, 2, Lijing Wu1, 2, Hong-tao Li1, Jin-qiu Zhou1, Chen Zhong1, Jianping Ding1, ,
Fanconi anemia (FA) is a chromosomal instability disorder associated with deficiencies in the Fanconi anemia complementation group (FANC) network. A complex consisting of FANCM-associated histone-fold proteins 1 and 2 (MHF1 and MHF2) has been shown to act cooperatively with FANCM in DNA damage repair in the FA pathway. Here we report the structure of Saccharomyces cerevisiae MHF complex in which MHF1 and MHF2 assume a typical histone fold, and the complex has a heterotetrameric architecture similar to that of the histones (H3-H4)2 heterotetramer. Loop L2 of MHF1 is probably involved in DNA binding, and loop L3 and helices α2 and α3 of one MHF1 subunit interact with those of the other to form two heterotetramer interfaces. Further genetic data demonstrate that the heterotetramer assembly is essential for the function of the complex in DNA repair. These results provide, to the best of our knowledge, new mechanistic insights into the function of the MHF complex.
