吴更
1.与癌症发生有关的蛋白质分子的结构生物学与生物化学研究;2.调节细菌的合成与分解代谢途径的重要蛋白质的结构生物学与生物化学研究;3.调控水稻发育的重要蛋白质的结构生物学与生物化学研究;4.基于蛋白质结构的研制开发抗癌药物的研究。
个性化签名
- 姓名:吴更
- 目前身份:
- 担任导师情况:
- 学位:
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学术头衔:
博士生导师, 教育部“新世纪优秀人才支持计划”入选者
- 职称:-
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学科领域:
生物化学
- 研究兴趣:1.与癌症发生有关的蛋白质分子的结构生物学与生物化学研究;2.调节细菌的合成与分解代谢途径的重要蛋白质的结构生物学与生物化学研究;3.调控水稻发育的重要蛋白质的结构生物学与生物化学研究;4.基于蛋白质结构的研制开发抗癌药物的研究。
吴更
工作、学习简历:
1992到1997年在中国科学技术大学试点班(零零班)与生物系学习,主修分子生物学专业,辅修化学物理学专业,获得学士学位。1997到2001年在美国普林斯顿大学化学系学习,在分子生物系施一公教授实验室做毕业论文,从事与癌症相关的TGF-beta信号传导通路与细胞凋亡通路中蛋白质分子复合物的X射线晶体结构生物学与生物化学研究,获得硕士与博士学位。2001到2003年在美国Memorial Sloan Kettering癌症研究所Nikola Pavletich教授实验室(附属于Howard Hughes Medical Institute)做博士后,从事与癌症相关的泛素化通路中蛋白质分子复合物的X射线晶体结构生物学与生物化学研究。2003到2008年在哈佛大学医学院贺熹教授实验室做资深博士后(special fellow),从事与癌症相关的Wnt信号传导通路的生物化学研究。2008年起全职回国,在上海交通大学生命科学技术学院任教授、博士生导师。2005年,获美国“白血病与淋巴癌学会”的special fellowship。2008年,获上海市“东方学者特聘教授”称号和上海市“曙光学者”称号。发表SCI论文11篇,论文被引用总计965次。其中作为第一作者在Nature、Molecular Cell和Science上发表的蛋白质晶体结构的论文分别被引用326次、166次和120次。所解析的晶体结构被许多世界大型制药公司如Genentech、Novartis、Amgen等作为寻找抗癌药物的参考依据,现在找到的某些化合物已经被用于临床试验。
研究方向:
1.与癌症发生有关的蛋白质分子的结构生物学与生物化学研究;
2.调节细菌的合成与分解代谢途径的重要蛋白质的结构生物学与生物化学研究;
3.调控水稻发育的重要蛋白质的结构生物学与生物化学研究;
4.基于蛋白质结构的研制开发抗癌药物的研究。
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吴更, Geng Wu¤*, He Huang, Jose Garcia Abreu, , Xi He*
March 2009|Volume 4|Issue 3|e4926,-0001,():
-1年11月30日
The Wnt/β-catenin signaling pathway plays essential roles in cell proliferation and differentiation, and deregulated β-catenin protein levels lead to many types of human cancers. On activation by Wnt, the Wnt co-receptor LDL receptor related protein 6 (LRP6) is phosphorylated at multiple conserved intracellular PPPSPXS motifs by glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1), resulting in recruitment of the scaffolding protein Axin to LRP6. As a result, β-catenin phosphorylation by GSK3 is inhibited and β-catenin protein is stabilized. However, how LRP6 phosphorylation and the ensuing LRP6-Axin interaction lead to the inhibition of β-catenin phosphorylation by GSK3 is not fully understood. In this study, we reconstituted Axin-dependent β-catenin phosphorylation by GSK3 and CK1 in vitro using recombinant proteins, and found that the phosphorylated PPPSPXS peptides directly inhibit β-catenin phosphorylation by GSK3 in a sequence and phosphorylation-dependent manner. This inhibitory effect of phosphorylated PPPSPXS motifs is direct and specific for GSK3 phosphorylation of β-catenin at Ser33/Ser37/Thr41 but not for CK1 phosphorylation of b-catenin at Ser45, and is independent of Axin function. We also show that a phosphorylated PPPSPXS peptide is able to activate Wnt/β-catenin signaling and to induce axis duplication in Xenopus embryos, presumably by inhibition of GSK3 in vivo. Based on these observations, we propose a working model that Axin recruitment to the phosphorylated LRP6 places GSK3 in the vicinity of multiple phosphorylated PPPSPXS motifs, which directly inhibit GSK3 phosphorylation of β-catenin. This model provides a possible mechanism to account, in part, for inhibition of β-catenin phosphorylation by Wnt-activated LRP6.
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吴更, Jingchen Li a, Jinhui Feng a, Qian Li a, Cuiqing Maa, Bo Yub, Chao Gao a, Geng Wuc, Ping Xu a, c, *
Bioresource Technology 100(2009)2594-2599,-0001,():
-1年11月30日
To investigate the flavin utilization by dibenzothiophene monooxygenase (DszC), DszC of a desulfurizing bacterium Mycobacterium goodii X7B was purified from the recombinant Escherichia coli. It was shown to be able to utilize either FMNH2 or FADH2 when coupled with a flavin reductase that reduces either FMN or FAD. Sequence analysis indicated that DszC was similar to the C2 component of p-hydroxyphenylacetate hydroxylase from Acinetobacter baumannii, which can use both FADH2 and FMNH2 as substrates. Both flavins at high concentrations could inhibit the activity of DszC due to autocatalytic oxidation of reduced flavins. The results suggest that DszC should be reclassified as an FMNH2 and FADH2 both-utilizing monooxygenase component and the flavins should be controlled at properly reduced levels to obtain optimal biodesulfurization results.
Dibenzothiophene monooxygenase FMNH2 FADH2 Biodesulfurization Mycobacterium goodii
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吴更, Geng Wu and Xi He*
Biochemistry 2006, 45, 5319-5323,-0001,():
-1年11月30日
β-Catenin phosphorylation at serine 45 (Ser45), threonine 41 (Thr41), Ser37, and Ser33 is critical for β-catenin degradation, and regulation of β-catenin phosphorylation is a central part of the canonical Wnt signaling pathway. β-Catenin mutations at Ser45, Thr41, Ser37, and Ser33 perturb β-catenin degradation and are frequently found in cancers. It is established that Ser45 phosphorylation by casein kinase I (CKI) initiates phosphorylation at Thr41, Ser37, and Ser33 by glycogen synthase kinase 3 (GSK3) and that phosphorylated Ser37 and Ser33 are recognized by the F-box protein β-TrCP, a component of a ubiquitin ligase complex that mediates β-catenin degradation. While the roles of Ser45, Ser37, and Ser33 are well documented, the function of Thr41 remains less defined. Here we show that Thr41 strictly acts as a phosphorylation relay residue and that the Ser-X-X-X-Ser (X is any amino acid) motif is obligatory for β-catenin phosphorylation by GSK3. β-Catenin phosphorylation/degradation and its regulation by Wnt can occur normally in the absence of Thr41 as long as the Ser-X-X-X-Ser motif/spacing is preserved. These results suggest that Thr41 functions to bridge sequential phosphorylation from Ser45 to Ser37 and provide further insights into the discrete steps and logic in β-catenin phosphorylation-degradation.
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【期刊论文】Structural Basis of the Cks1-Dependent Recognition of p27Kip1 by the SCFSkp2 Ubiquitin Ligase
吴更, Bing Hao, , Ning Zheng, Brenda A. Schulman, Geng Wu, Julie J. Miller, Michele Pagano, and Nikola P. Pavletich, *
Molecular Cell, Vol. 20, 9-19, October 7, 2005,-0001,():
-1年11月30日
The ubiquitin-mediated proteolysis of the Cdk2 inhibitor p27Kip1 plays a central role in cell cycle progression, and enhanced degradation of p27Kip1 is associated with many common cancers. Proteolysis of p27Kip1 is triggered by Thr187 phosphorylation, which leads to the binding of the SCFSkp2 (Skp1-Cul1-Rbx1-Skp2) ubiquitin ligase complex. Unlike other known SCF substrates, p27Kip1 ubiquitination also requires the accessory protein Cks1. The crystal structure of the Skp1-Skp2-Cks1 complex bound to a p27Kip1 phosphopeptide shows that Cks1 binds to the leucine-rich repeat (LRR) domain and C-terminal tail of Skp2, whereas p27Kip1 binds to both Cks1 and Skp2. The phosphorylated Thr187 side chain of p27Kip1 is recognized by a Cks1 phosphate binding site, whereas the side chain of an invariant Glu185 inserts into the interface between Skp2 and Cks1, interacting with both. The structure and biochemical data support the proposed model that Cdk2-cyclin A contributes to the recruitment of p27Kip1 to the SCFSkp2-Cks1 complex.
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【期刊论文】Ozz: A New Name on the Long List of β-Catenin's Nemeses
吴更, Geng Wu, Chunming Liu, and Xi He
Molecular Cell, Vol. 13, 451-458, February 27, 2004,-0001,():
-1年11月30日
In the February issue of Developmental Cell, Nastasi et al. describe Ozz, a muscle-specific ubiquitin ligase adaptor that regulates myofibril organization. Ozz appears to function in ubiquitination and degradation of membrane-bound, but not eytosolie, β-eatenin,whose turnover may be required for alignment and growth of the sareomere, the basic contractile unit of myofibers.
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吴更, Geng Wu, , Guozhou Xu, Brenda A. Schulman, Philip D. Jeffrey, J. Wade Harper, and Nikola P. Pavletich, *
Molecular Cell, Vol. 11, 1445-1456, June, 2003,-0001,():
-1年11月30日
The SCF ubiquitin ligases catalyze protein ubiquitination in diverse cellular processes. SCFs bind substrates through the interchangeable F box protein subunit, with the 70 human F box proteins allowing the recognition of a wide range of substrates. The F box protein β-TrCP1 recognizes the doubly phosphorylated DpSGφXpS destruction motif, present in β-catenin and I B, and directs the SCF β-TrCP1 to ubiquitinate these proteins at specific lysines. The 3.0 A structure of a β-TrCP1-Skp1-β-catenin complex reveals the basis of substrate recognition by the β-TrCP1 WD40 domain. The structure, togetherwith the previous SCFSkp2 structure, leads to the model of SCF catalyzing ubiquitination by increasing the effective concentration of the substrate lysine at the E2 active site. The model's prediction that the lysine-destruction motif spacing is a determinant of ubiquitination efficiency is confirmed by measuring ubiquitination rates of mutant β-catenin peptides, solidifying the model and also providing a mechanistic basis for lysine selection.
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