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  • 周小龙
  • 研究员，研究组长,博士生导师
  • E-mail: xlzhou@sibcb.ac.cn
  • 实验室主页: 
    个人简介：

  • 　　2004年7月毕业于安徽师范大学生命科学学院，获得理学学士学位;2009年5月毕业于中国科学院上海生命科学研究院，获得理学博士学位。2009年6月至2017年10月，任中科院生化与细胞所助理研究员、副研究员;2009年11月至2010年1月，法国国家科研中心(CNRS)斯特拉斯堡分子与细胞生物学研究所访问学者;2010年7月至2010年12月，美国耶鲁大学分子生物物理与生物化学系访问学者;2017年11月起任生化与细胞所研究员;2019年5月起，任生化与细胞所研究组长、博士生导师。荣获2011年度中科院卢嘉锡青年人才奖、中科院青年创新促进会会员、2012年度赛诺菲-中科院上海生科院优秀青年人才奖、2015年度中科院青年创新促进会优秀会员、2016年度上海市青年科技启明星、2018年度国家自然科学基金优秀青年基金等人才项目或称号。

    社会任职：
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    研究方向：
  • 蛋白质生物合成的分子基础与相关疾病
    研究工作：

  • 　　蛋白质合成是细胞内最为重要、复杂的生命活动之一，是一切生命活动的基础。氨基酰-tRNA合成酶(AARS)蛋白质家族以氨基酸、ATP、tRNA作为底物，生成氨基酰-tRNA(该反应称为氨基酰化反应)，为蛋白质合成提供原料。高等真核生物(例如人类)具有细胞质与线粒体两个蛋白质合成系统。主要以人AARS及tRNA作为研究对象，开展以下几方面的研究：

    　　(1) AARS经典功能与非经典功能的研究

    　　蛋白质合成中，AARS从源头上介导氨基酸与tRNA之间的精确匹配，生成正确的氨基酰-tRNA，为核糖体提供原料。AARS需要高效地催化氨基酰化反应以合成正确的氨基酰-tRNA，满足蛋白质合成速率; AARS同时需要通过水解编校反应以确保氨基酸与tRNA的正确匹配。匹配错误生成的误氨基酰-tRNA进入核糖体后，会导致整个蛋白质组发生错误翻译，导致多种人类疾病。氨基酰化反应与编校反应是AARS的经典功能，分别控制蛋白质合成的速率与保真性，对于细胞生命活动具有至关重要的作用。由于AARS分布广谱性、结构或机制差异性，通过研究不同种属(尤其是病原菌和人)来源的AARS的催化机制，可以基于结构或功能差异，设计专一抑制病原菌AARS的抗生素而达到治疗人类疾病的目的。另一方面，人AARS在进化过程中，在主体结构外普遍招募了各种延伸或插入结构域，介导了包括血管发生、转录或翻译调控、癌症发生、细胞代谢、免疫应答等一系列蛋白质合成以外的新功能，统称为非经典功能。我们将以哺乳动物AARS最为研究对象，研究其介导的经典功能以及非经典功能的分子机制。

    　　(2) AARS或线粒体tRNA基因突变导致人类相关疾病的分子基础

    　　线粒体翻译所有蛋白质组分(例如19种线粒体AARS等)由核基因组编码，而核酸组分(例如22种线粒体tRNA等)由线粒体基因组编码。线粒体相关的核基因突变以及线粒体自身基因突变主要影响中枢神经系统及肌肉系统，导致线粒体功能异常，造成人类疾病，统称为线粒体病(例如神经退行性疾病、心脏病、脑白质病变、耳聋等)。细胞质与线粒体AARS突变导致人类疾病。特别的是，迄今已发现约400种导致线粒体病的线粒体基因突变，而超过275种(>60%)定位于22种线粒体tRNA基因中，且所有导致疾病的tRNA基因突变全部位于线粒体tRNA，该类疾病统常呈现母系遗传(非孟德尔遗传)特征。拟主要鉴定疾病中AARS或tRNA致病点突变、研究由AARS或线粒体tRNA基因突变导致人类疾病的分子机理。

    　　(3) tRNA修饰的分子机制及其与人类相关疾病

    　　RNA的转录后修饰具有重要的生物学意义。发生在tRNA上的转录后修饰种类最多，机制最为多样与复杂。tRNA的转录后修饰对于其结构、稳定性、基因信息传递的速率与精确性、蛋白质稳态平衡、细胞功能的正常发挥具有重要的意义。tRNA修饰的紊乱导致多种疾病。拟主要鉴定人细胞质或线粒体tRNA修饰酶、研究其修饰的分子机理、研究修饰酶及tRNA基因突变对于修饰、线粒体及细胞功能的影响。

    承担科研项目情况：
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    代表论著：
    1. Peng GX#, Mao XL#, Cao YT, Yao SY, Li QR, Chen X, Wang ED*, Zhou XL*, RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation. Nucleic Acids Res., 2022, 50(22): 12951-12968.
    2. Yu T#, Zhang Y#, Zheng WQ, Wu S, Li G, Zhang Y, Li N, Yao R, Fang P, Wang J*, Zhou XL*, Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease. Nucleic Acids Res., 2022, 50(20):11755-11774.
    3. Huang MH, Peng GX, Mao XL, Wang JT, Zhou JB, Zhang JH, Chen M, Wang ED*, Zhou XL*. Molecular basis for human mitochondrial tRNA m3C modification by alternatively spliced METTL8. Nucleic Acids Res., 2022, 50(7):4012-4028.
    4. Wu S, Zheng L, Hei Z, Zhou JB, Li G, Li P, Wang J, Ali H, Zhou XL, Wang J, Fang P. Human lysyl-tRNA synthetase evolves a dynamic structure that can be stabilized by forming complex. Cell. Mol. Life Sci., 2022, 79(2):128.
    5. Wang JT#, Zhou JB#, Mao XL, Zhou L, Chen M, Zhang W, Wang ED*, Zhou XL*. Commonality and diversity in tRNA substrate recognition in t6A biogenesis by eukaryotic KEOPSs. Nucleic Acids Res., 2022, 50(4):2223-2239.
    6. Zheng WQ, Pedersen SV, Thompson K, Bellacchio E, French CE, Munro B, Pearson TS, Vogt J, Diodato D, Diemer T, Ernst A, Horvath R, Chitre M, Ek J, Wibrand F, Grange DK, Raymond L, Zhou XL*, Taylor RW, Ostergaard E*. Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease, Hum Mol Genet., 2022, 31(4):523-534.
    7. Chen R, Zhou J, Liu L, Mao XL, Zhou XL, Xie W. Crystal structure of human METTL6, the m3C methyltransferase. Commun. Biol., 2021, 4(1):1361.
    8. Zhou JB, Wang ED*, Zhou XL*. Modifications of the human tRNA anticodon loop and their associations with genetic diseases. Cell. Mol. Life Sci., 2021, 78(23):7087-7105.
    9. Zhang F#, Zeng QY#, Xu H#, Xu A#, Liu DJ, Li NZ, Chen Y, Jin Y, Xu CH, Feng CZ, Zhang YL, Liu D, Liu N, Xie Y, Yu SH, Yuan H, Xue K, Shi JY, Liu T, Xu PF, Zhao WL, Zhou Y, Wang L, Huang QH, Chen Z, Chen SJ*, Zhou XL*, Sun XJ*. Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis. Cell Discovery, 2021, 7(1):98.  
    10. Mao XL, Li ZH, Huang MH, Wang JT, Zhou JB, Li QR, Xu H, Wang XJ, Zhou XL*. Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6. Nucleic Acids Res., 2021, 49(14): 8309-8323.
    11. Peng GX, Zhang Y, Wang QQ, Li QR, Xu H, Wang ED*, Zhou XL*. The human tRNA taurine modification enzyme GTPBP3 is an active GTPase linked to mitochondrial diseases. Nucleic Acids Res., 2021, 49(5): 2816–2834.
    12. Li G, Eriani G, Wang ED*, Zhou XL*. Distinct pathogenic mechanisms of various RARS1 mutations in Pelizaeus-Merzbacher-like disease. Sci. China Life Sci., 2021, 64(10):1645-1660.
    13. Zheng WQ#, Zhang Y#, Yao Q#, Chen Y#, Qiao XH, Wang ED*, Chen C*, Zhou XL*. Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation. Nucleic Acids Res., 2020, 48(12):6799-6810.
    14. Zhou JB, Wang Y, Zeng QY, Meng SX, Wang ED*, Zhou XL*. Molecular basis for t6A modification in human mitochondria. Nucleic Acids Res., 2020, 48(6):3181-3194.
    15. Wang Y#, Zhou JB#, Zeng QY, Wu S, Xue MQ, Fang P, Wang ED*, Zhou XL*. Hearing impairment-associated KARS mutations lead to defects in aminoacylation of both cytoplasmic and mitochondrial tRNALys. Sci. China Life Sci., 2020, 63(8):1227-1239.
    16. Zhou XL#,*, Chen Y#, Zeng QY, Ruan ZR, Fang P, Wang ED*. Newly acquired N-terminal extension targets threonyl-tRNA synthetase-like protein into the multiple tRNA synthetase complex. Nucleic Acids Res., 2019, 47(16), 8662-8674.
    17. Zeng QY, Peng GX, Li G, Zhou JB, Zheng WQ, Xue MQ, Wang ED*, Zhou XL*. The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase. Nucleic Acids Res., 2019, 47(6), 3072-3085.
    18. Wang Y, Zeng QY, Zheng WQ, Ji QQ, Zhou XL*, Wang ED*. A natural non-Watson-Crick base pair in human mitochondrial tRNAThr causes structural and functional susceptibility to local mutations. Nucleic Acids Res., 2018, 46(9), 4662-4676.
    19. Chen Y, Ruan ZR, Wang Y, Huang Q, Xue MQ, Zhou XL*, Wang ED*. A threonyl-tRNA synthetase-like protein has tRNA aminoacylation and editing activities. Nucleic Acids Res., 2018, 46(7), 3643-3656.
    20. Hilander T#, Zhou XL#, Konovalova S, Zhang FP, Euro L, Chilov D, Poutanen M, Chihade J, Wang ED*, Tyynismaa H*. Editing activity for eliminating mischarged tRNAs is essential in mammalian mitochondria. Nucleic Acids Res., 2018, 46(2), 849-860.
    21. Zhou XL#, He LX#, Yu LJ#, Wang Y, Wang XJ*, Wang ED*, Yang T*. Mutations in KARS cause early-onset hearing loss and leukoencepha lopathy: Potential pathogenic mechanism. Human Mutation, 2017, 38(12):1740-1750.
    22. Zhou XL#, Chen Y#, Fang ZP, Ruan ZR, Wang Y, Liu RJ, Xue MQ, Wang ED*. Translational quality control by bacterial threonyl-tRNA synthetases. J. Biol. Chem., 2016, 291(40), 21208-21221.
    23. Wang Y#, Zhou XL#,*, Ruan ZR#, Liu RJ, Eriani G, Wang ED*. A human disease-causing point mutation in mitochondrial threonyl-tRNA synthetase induces both structural and functional defects. J. Biol. Chem., 2016, 291(12):6507-6520.
    24. Ji QQ, Fang ZP, Ye Q, Ruan ZR, Zhou XL*, Wang ED*. C-terminal domain of leucyl-tRNA synthetase from pathogenic Candida albicans recognizes both tRNASer and tRNALeu. J. Biol. Chem., 2016, 291(7):3613-3625.
    25. Ye Q, Wang M, Fang ZP, Ruan ZR, Ji QQ, Zhou XL*, Wang ED*. Degenerate CP1 domain from human mitochondrial leucyl-tRNA Synthetase. J. Biol. Chem., 2015, 290(40):24391-24402.
    26. Ruan ZR, Fang ZP, Ye Q, Lei HY, Eriani G, Zhou XL*, Wang ED*. Identification of lethal mutations in yeast threonyl-tRNA synthetase revealing critical residues in its human homolog. J. Biol. Chem., 2015, 290(3):1664-1678.
    27. Zhou XL, Ruan ZR, Wang M, Fang ZP, Wang Y, Chen Y, Liu RJ, Eriani G, Wang ED*, A minimalist mitochondrial threonyl-tRNA synthetase exhibits tRNA-isoacceptor specificity during proofreading. Nucleic Acids Res., 2014, 42(22):13873-13886.
    28. Fang ZP, Wang M, Ruan ZR, Tan M, Liu RJ, Zhou M, Zhou XL*, Wang ED*. Co-existence of bacterial leucyl-tRNA synthetases with archaeal tRNA binding domains that distinguish tRNALeu in the archaeal mode. Nucleic Acids Res., 2014, 42(8):5109-5124.
    29. Zhou XL and Wang ED*. Transfer RNA: a dancer between charging and mis-charging for protein biosynthesis. Sci. China Life Sci., 2013, 56(10):921-932. (Invited review)
    30. Zhou XL, Fang ZP, Ruan ZR, Wang M, Liu RJ, Tan M, Anella F, Wang ED*. Aminoacylation and translational quality control strategy employed by leucyl-tRNA synthetase from a human pathogen with genetic code ambiguity. Nucleic Acids Res., 2013, 41(21):9825-9838.
    31. Zhou XL, Ruan ZR, Huang Q, Tan M, Wang ED*. Translational fidelity maintenance preventing Ser mis-incorporation at Thr codon in protein from eukaryote. Nucleic Acids Res., 2013, 41(1):302-314.
    32. Zhou XL, Du DH, Tan M, Lei HY, Ruan LL, Eriani G, Wang ED*. Role of tRNA amino acid-accepting end in aminoacylation and its quality control. Nucleic Acids Res., 2011, 39(20):8857-8868.
    33. Zhou XL, Tan M, Wang M, Chen X, Wang ED*. Post-transfer editing by a eukaryotic leucyl-tRNA synthetase resistant to the broad-spectrum drug AN2690. Biochem J., 2010, 430(2):325-333.
    34. Zhou XL, Wang M, Tan M, Huang Q, Eriani G, Wang ED*. Functional characterization of leucine-specific domain 1 from eukaryal and archaeal leucyl-tRNA synthetases. Biochem J., 2010, 429(3):505-513.
    35. Zhou XL and Wang ED*. Two tyrosine residues outside the editing active site in Giardia lamblia leucyl-tRNA synthetase are essential for the post-transfer editing. Biochem. Biophys. Res. Commun., 2009, 386(3):510-515.
    36. Zhou XL, Yao P, Ruan LL, Zhu B, Luo J, Qu LH, Wang ED*. A unique peptide in the CP1 domain of Giardia lamblia leucyl-tRNA Synthetase. Biochemistry (US), 2009, 48(6):1340-1347.
    37. Zhou XL, Zhu B, Wang ED*. The CP2 domain of leucyl-tRNA synthetase is crucial for amino acid activation and post-transfer editing. J. Biol. Chem., 2008, 283(52):36608-36616.
    38. Zhou XL and Wang ED*, Mitochondrial aminoacyl-tRNA synthetases related to human diseases. Prog. Biochem. Biophys., 2008, 35(8):853-858. (Review)
    获奖及荣誉：
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    研究组成员：
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