8月15日,，國際雜志《生化期刊》（Biochemical Journal）發(fā)表了中科院上海生科院生物化學(xué)與細(xì)胞生物學(xué)研究所丁建平研究組關(guān)于核糖體S6激酶1 (ribosome protein subunit 6 kinase 1，S6K1) 功能調(diào)控機(jī)制的最新研究成果,，該研究成果得到同行審稿專家和雜志編輯的贊賞,。
mTOR信號通路在細(xì)胞生長、增殖以及代謝調(diào)控等生物學(xué)過程中發(fā)揮重要作用,，其功能異常與腫瘤,、代謝疾病以及發(fā)育缺陷等密切相關(guān)。丁建平組長期從事mTOR信號通路調(diào)控的分子機(jī)制研究,，取得了一系列重要成果,。S6K1是mTORC1的下游效應(yīng)分子之一，通過磷酸化多種底物參與眾多生理過程的調(diào)控,，包括基因轉(zhuǎn)錄,、mRNA剪接以及蛋白質(zhì)合成等。S6K1的激酶活性受到自身多個位點(diǎn)磷酸化修飾的調(diào)控,，包括疏水模體（HM）上Thr389和活化環(huán)區(qū)Thr229的磷酸化,，但其分子機(jī)制并不清楚。
丁建平組博士生王建船等人解析了6個S6K1催化結(jié)構(gòu)域自身及其融合HM區(qū)域與特異小分子抑制劑形成的復(fù)合物的晶體結(jié)構(gòu),。結(jié)構(gòu)分析表明,，HM通過疏水和親水相互作用結(jié)合在N-lobe的疏水性口袋中，其中兩個高度保守的氨基酸殘基Gln140和Arg121,，在親水相互作用網(wǎng)絡(luò)中發(fā)揮重要作用,，穩(wěn)定了催化結(jié)構(gòu)域的構(gòu)象。進(jìn)一步的生化和細(xì)胞生物學(xué)實(shí)驗(yàn)結(jié)果顯示,，體內(nèi)S6K1上Thr389的磷酸化可在Th229未磷酸化時進(jìn)行,，而且Thr389的磷酸化或者模擬磷酸化的突變體能夠通過氫鍵增強(qiáng)HM與N-lobe的相互作用。此外,，還發(fā)現(xiàn)活化環(huán)區(qū)上存在一個非典型的,、可能為S6K1特有的鋅指結(jié)構(gòu)域，為S6K1的調(diào)節(jié)機(jī)制研究提供了新思路,。研究結(jié)果進(jìn)一步加深了對S6K1調(diào)控機(jī)制的理解,，同時還為設(shè)計(jì)和改造S6K1特異性的小分子抑制劑提供了線索。
該課題得到了國家科技部,、國家自然科學(xué)基金委,、中國科學(xué)院和上海市科委的經(jīng)費(fèi)支持,。（生物谷Bioon.com）
doi:10.1042/BJ20121863
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Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif.
Wang J, Zhong C, Wang F, Qu F, Ding J.
The activity of S6K1 (p70 ribosomal protein subunit 6 kinase 1) is stimulated by phosphorylation of Thr389 in the hydrophobic motif by mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of Thr229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1); however, the order of the two events is still ambiguous. In the present paper we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data, together with the biochemical data, reveal in vivo phosphorylation of Thr389 in the absence of Thr229 phosphorylation and demonstrate the importance of two conserved residues, Gln140 and Arg121, in the establishment of a hydrogen-bonding network between the N-lobe (N-terminal lobe) and the hydrophobic motif. Phosphorylation of Thr389 or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix αC. Furthermore, comparisons of S6K1 with other AGC (protein kinase A/protein kinase G/protein kinase C) family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix αC account for their divergence in PDK1 dependency. Taken together, the results of the present study indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of, and probably precedes and promotes, phosphorylation of the activation loop.
