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专家类别: 院士,研究员
简历 & 研究组工作摘要：
1964年开始在生物物理所从事蛋白质研究
现为结构生物学与分子生物学研究中心研究员
中国科学院院士，发展中国家科学院（TWAS）院士
生物大分子国家重点实验室学术委员会主任
中国生物化学与分子生物学学会蛋白质专业委员会主任
主要研究方向
本研究室近十几年来集中在蛋白质折叠研究，在国内开辟了分子伴侣和折叠酶研究的新方向。提出“蛋白质二硫键异构酶（PDI）既是酶又是分子伴侣”的假说，为此假说提供了实验支持；系统研究了一些分子伴侣和酶的两种活性的结构基础和作用机制，建立了折叠酶帮助蛋白质折叠较全面的作用模式。蛋白质二硫键异构酶在体内的分子伴侣功能已得到国际上越来越多的实验证据。本研究室近年来深入研究蛋白质氧化折叠机制以及分子伴侣在蛋白质质量控制中的作用。
近期（2006-2009）主要工作和进展
主要进展
1. 报道了用小角X射线散射技术测定的人PDI全长分子在溶液中四个亚基成环形排布，而非如美国同行推测的线性排布。该模型解释了PDI发挥生物活性合理的结构基础。J. Biol. Chem.（2006）
2. 鉴定了分子伴侣Hsp70通过与帕金森氏病相关蛋白α-synuclein的不同折叠中间体的相互作用抑制其形成纤维。J. Mol. Biol.（2006）。PDI的a’结构域在抑制α-synuclein成纤维过程中起关键作用。Cell Stress & Chaperones （2009）
3. 鉴定到细菌二硫键异构酶（DsbC）解折叠过程中的单体折叠中间体。Biochemistry(USA)（2006）。报道了热诱导DsbC解聚成单体产生氧化酶活性。Biophysical J. （2009）
4. 确认无信号肽的α-synuclein在大肠杆菌表达时转运到周质腔定位，并鉴定其C端99-140是主要的与转运相关的序列。J. Bacteriol.（2008）
5. 解析了人ERp44 2.6埃分辨率的晶体结构，提出ERp44的C端尾巴在蛋白质质量控制过程中动态调控底物蛋白的结合与释放。EMBO Rep.（2008）
6. 重构了人细胞内质网中的Ero1α/PDI氧化折叠系统，发现Ero1α在该系统中偏向于氧化PDI 的a’结构域的活性中心。鉴定了PDI同Ero1α相互作用的最小结构元件是b’xa’结构域，J. Biol. Chem.（2009）
7. 采用单分子荧光共振能量转移技术研究了金黄色葡萄球菌核酸酶的折叠机制。J. Phys. Chem. B.（2009）
目前主要工作
1. PDI的构象变化与氧化还原调控
2. Ero1/PDI氧化折叠系统的电子传递与调控机制
3. 巯基氧化酶QSOX在蛋白质氧化折叠和质量控制中的作用
4. 小热休克蛋白Hsp27抑制α-synuclein成纤维的作用机制
5．运用果蝇帕金森氏病模型揭示II型组蛋白去乙酰化酶HDAC6通过促进α-synuclein形成包含体从而减少高聚体而减少α-synuclein对神经细胞的毒性。
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Biography & Introduction
Zhizhen (Chih-chen) Wang, Professor and Director of the Academic Committee, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences; Member of the Chinese Academy of Sciences and the Academy of Sciences for the Developing World .
Zhizhen Wang graduated from the Department of Biophysics, University of Science and Technology of China, in 1964. She worked in Deutsches Wollforschungsinstitut and Georg-August-Universitāt, Gōtingen in Germany; NIDDK, NIH, City of Hope National Medical Center, FAD in USA; Alberta University in Canada; and Hong Kong University of Science and Technology, as a visiting scholar. She was the Chinese delegate to the Federation of Asia and Oceania for Biochemistry and Molecular Biology.
Zhizhen Wang received recognition for her research on protein folding, folding enzymes and molecular chaperones, as well as the interactions of insulin A and B chains.
Awards and honors:
The Third World Academy of Sciences Prize in Basic Sciences (Biology); The National Natural Science Award, twice; The Academy Natural Science Award twice; The Science and Technology Advancement Award of the Ho Leung Ho Lee Foundation; the Title of "Young and Middle Age Specialist with Outstanding Contributions in China ";"Top 10 Women Elite in China"
Research interests
1. Structure and function of molecular chaperones and folding enzymes. Focus on redox-proteins with chaperone and enzyme activities responsible for oxidative folding of proteins in the ER.
2. Fibril formation of neurodegenerative diseases-related proteins and the effect of chaperones on it.
3. Relationship of protein quality control system and Pathogenesis of Parkinson's disease in transgenic Drosophila model.
4. Protein folding and unfolding studied by using techniques of single molecule, FRET, FTIR etc.
2006-2007 work progress
Major progress
1. We presented for the first time a small angle X-ray scattering study of intact human protein disulfide isomerase. The four thioredoxin-fold domains are arranged in an annular but not in a linear fashion. Our model accounted for the cooperative properties of the four domains in both the isomerase and chaperone functions. J. Biol. Chem. (2006).
2. Heat shock protein 70 inhibits α-synuclein fibril formation via interactions with diverse intermediates formed during fibril formation. J. Mol. Biol.（2006）.Domain a’ of PDI was found to be essential and sufficient to inhibit α-synuclein fibril formation.，Cell Stress Chaperones （2009）
3. We characterized a monomeric folding intermediate of E. coli protein disulfide isomerase DsbC. Biochemistry (USA) (2006). The oxidase activity attributed to the monomer has been observed by thermal-induced dissociation of DsbC dimmer. Biophysical J. (2009)
4. Recombinant α-synuclein with no signal sequence produced in E. coli mostly localizes in the periplasm. The C-terminal 99-140 sequence is a major part responsible for the translocation, and the 1-60 sequence is not required. J. Bacteriol (2007)
5. We resolved the crystal structure of human ERp44 at 2.6 angstrom and suggested that ERp44 C-tail dynamically regulating substrate binding and release during protein quality control. EMBO Rep. (2008)
6. We reconstituted the Ero1α/PDI oxidative folding system in vitro and found that Ero1α prefers to oxidize the active site in the a’ domain of PDI. The minimal element for binding with Ero1α was mapped to the b’xa’ fragment of PDI. J. Biol. Chem. (2009)
7. We investigated the equilibrium denaturation of staphylococcal nuclease (SNase) by single molecule fluorescence resonance energy transfer. J. Phys. Chem. B. (2009)
Present works
1. The conformational change and redox regulation of PDI
2. The electron transfer and activity regulation of Ero1/PDI oxidative folding system
3. The role of QSOX in protein oxidative folding and quality control
4. The mechanism for the inhibition of α-synuclein fibril formation by the small heat shock protein Hsp27.
5. Studies on the function of HDAC6 in pathogenesis of Parkinson’s disease by using Drosophila PD model.
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Selected Publications：
1. H. Cheng, L. Wang & C. C. Wang*. (2009) Domain a' of protein disulfide isomerase plays key role in inhibiting alpha-synuclein fibril formation.Cell Stress Chaperones. [Epub ahead of print]
2. H. Li, H. M. Ke, G. P. Ren, X. G. Qiu, Y. X. Weng & C. C. Wang* (2009) Thermal-Induced Dissociation and Unfolding of Homodimeric DsbC Revealed by Temperature-Jump Time-Resolved Infrared Spectra. Biophysical Journal, 97, 2811-2819.
3. P. C. Liu, X. L. Meng, P. Qu, X. S. Zhao & C. C. Wang* (2009) Subdomain-Specific Collapse of Denatured Staphylococcal Nuclease Revealed by Single Molecule Fluorescence Resonance Energy Transfer Measurements. Journal of Physical Chemistry B, 113, 12030-12036.
4. L. Wang, S. J. Li, A. Sidhu, L. Zhu, Y. Liang, R. B. Freedman & C. C. Wang* (2009) Reconstitution of Human Ero1-L alpha/Protein-Disulfide Isomerase Oxidative Folding Pathway in Vitro: POSITION-DEPENDENT DIFFERENCES IN ROLE BETWEEN THE a AND a ' DOMAINS OF PROTEIN-DISULFIDE ISOMERASE. J Biol Chem, 284, 199-206.
5. L. K. Wang, L. Wang, S. Vavassori, S. J. Li, H. M. Ke, T. Anelli, M. Degano, R. Ronzoni, R. Sitia, F. Sun & C. C. Wang* (2008) Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail. EMBO reports, 9, 642–647.
6. G. P. Ren, X. Wang, S. F. Hao, H. Y. Hu & C. C. Wang* (2007) Translocation of α-Synuclein expressed in Escherichia coli. J. Bacteriol. 189, 2777-2786.
7. H. M. Ke, S. Zhang, J. Li, G. J. Howlett & C. C. Wang* （2006）Folding of Escherichia coli DsbC: Characterization of a Monomeric Folding Intermediate. Biochemistry (USA) 45, 15100-15110.
8. C. J. Huang, H. Cheng, S. F. Hao, H. Zhou, X. J. Zhang, J. E. Gao, Q. H. Sun, H. Y. Hu & C. C. Wang* （2006）Heat Shock Protein 70 Inhibits α-Synuclein Fibril Formation via Interactions with Diverse Intermediates. J. Mol. Biol., 364, 323-336.
9. S. J. Li, X. G. Hong, Y. Y. Shi, H. Li & C. C. Wang* (2006) Annual arrangement and collaborative actions of four domains of protein disulfide isomerase - A Small angle X-ray scattering study in solution. J. Biol. Chem., 281, 6581-6588.
10. Y. Y. Shi, X. G. Hong & C. C. Wang* (2005) The C-terminal (331-376) sequence of Escherichia coli DnaJ is essential for dimerization and chaperone activity: A small angle X-ray scattering study in solution. J. Biol. Chem., 280, 22761-22768.
11. Z. Zhao, Y. Peng, S. F. Hao, Z.H. Zeng & C. C. Wang* (2003) Dimerization by domain hybridization bestows chaperone and isomerase activities. J. Biol. Chem., 278, 43292-43298.
12. X. Q. Liu & C. C. Wang* (2001) Disulfide-dependent folding and export of Escherichia coli DsbC. J. Biol. Chem. 276, 1146-1151.
13. J. Li, S. Zhang & C. C. Wang* (2001) Effects of macromolecular crowding on the refolding of glucose-6-phosphate dehydrogenase and protein disulfide isomerase. J. Biol. Chem., 276, 4396-34401.
14. X. X. Sun & C. C. Wang* (2000) The N-terminal sequence of (residues 1-65) is essential for dimerization, activity and peptide binding of Escherichia coli DsbC. J. Biol. Chem. 275, 22743-22749.
15. J. Li & C. C. Wang* (1999) “Half of the sites” binding of D-glyceraldehyde-3-phosphate dehydrogenase folding intermediate with GroEL. J. Biol. Chem. 274, 10790-10794.
16. J. Chen, J. L. Song, S. Zhang, Y. Wang, D. F. Cui & C. C. Wang* (1999) Chaperone activity of DsbC. J. Biol. Chem. 274, 19601-19604.
17. Y. Dai & C. C. Wang* (1997) A mutant truncated protein disulfide isomerase with no chaperone activity. J. Biol. Chem. 272, 27572-27576.
18. Y. Yao, Y. C. Zhou & C. C. Wang* (1997) Both the isomerase and chaperone activities of protein disulfide isomerase are required for the reactivation of reduced and denatured acidic phospholipase A2. EMBO J. 16, 651-658.
19. H. Quan, G. Fan & C. C. Wang* (1995) Independence of the chaperone activity of protein disulfide isomerase from its thioredoxin-like active site. J. Biol. Chem. 270, 17078-17080.
20. H. Cai., C. C. Wang* & C. L. Tsou (1994) Chaperone-like activity of protein disulfide isomerase in the refolding of a protein with no disulfide bounds. J. Biol. Chem. 269, 24550-24552.
21. C. C. Wang & C. L. Tsou (1993) Protein disulfide isomerase is both an enzyme and a chaperone. FASEB J. 7, 1515-1517.
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