研领域描述
Mechanisms of protein biogenesis, folding, disulfide bond formation, and degradation (protein quality control)
A wide variety of molecular chaperones, folding catalysts and proteases play critical roles in the quality control of thousands of proteins in living cells. We specifically focus on the quality control of outer membrane proteins (OMPs) in gram-negative bacteria (E.coli), and investigate the action mechanisms of several key factors like DegP, SurA and Skp in assisting the folding and assembly of OMPs. To look at their roles in living cells, a new strategy, i.e, in vivo photo-cross-linking by non-natural amino acids, has been explored to characterize the substrate protein-binding sites of DegP, SurA and Skp, as well as to identify their natural substrate proteins. The ultimate goal is to be able to elucidate the protein quality control mechanisms of OMPs mediated by chaperone and protease factors and thus potentially assist the development of new antibacterial drugs interfering protein quality control processes
A key issue regarding the quality control of secretory proteins (e.g. periplasmic proteins in E.coli) is to form correct disulfide bonds. The second focus of my research is to understand mechanisms of protein folding catalysts-mediated disulfide bond formation. We are particularly interested in three folding catalysts: E.coli DsbA, E.coli DsbC, and human PDI. The goal is to elucidate how these key catalysts recognize and interact with a wide range of natural substrate proteins that are quite different with respect to molecular size, hydrophobicity and folding state and so on.
代表性论文
1. Fu X*, Chang Z, Shi X, Bu D, Wang C. , Multilevel structural characteristics for the natural substrate proteins of bacterial small heat shock proteins. , Protein Sci. , 2014 , 23: 229-237 , [Full Text] , *corresponding author
2. Xi Ge, Rui Wang, Jing Ma, Yang Liu, Anastasia N. Ezemaduka, Peng R. Chen, Xinmiao Fu* and Zengyi Chang* , DegP primarily functions as a protease for the biogenesis of β-barrel outer membrane proteins in Gram-negative bacterium Escherichia coli , FEBS J , 2014 , 281: 1226-1240. , *co-corresponding author
3. Xi Ge, Zhi-Xin Lyu, Yang Liu, Rui Wang, Xin Sheng Zhao, Xinmiao Fu* and Zengyi Chang* , Identification of FkpA as a key quality control factor for the biogenesis of outer membrane proteins under heat shock conditions , J. Bacteriol. , 2014 , 196: 672-680 , [Abstract] , *co-corresponding author
4. Xinmiao Fu , Chaperone function and mechanism of small heat shock proteins , Acta Biochimica et Biophysica Sinica (ABBS) , 2014 , 46(5):347-56 (editor-invited review)
5. Anastasia N Ezemaduka, Jiayu Yu, Xiaodong Shi, Kaiming Zhang, Chang-Cheng Yin, Xinmiao Fu ? and Zengyi Chang* , A small heat shock protein enables Escherichia coli to grow at a lethal temperature of 50oC conceivably by maintaining cell envelope integrity , J. Bacteriol. , 2014 , 196(11):2004-11 , *co-corresponding author
6. Xinmiao Fu*, Xiaodong Shi, Linxuan Yan, Hanlin Zhang, and Zengyi Chang* , In vivo substrate diversity and preference of small heat shock protein IbpB as revealed by using a genetically incorporated photo-crosslinker , J. Biol. Chem. , 2013 , 288: 31646-54. , [Full Text] , *co-corresponding author
7. Fu X*, Shi X, Yin L, Liu J, Joo K, Lee J, Chang Z.* , Small heat shock protein IbpB acts as a robust chaperone in living cells by hierarchically activating its multi-type substrate-binding residues. , J Biol Chem , 2013 , Apr 26;288(17):11897-906. *co-corresponding author , [Full Text]
8. Xinmiao Fu, Pan Wang, Masayuki Fukui, Cheng Long, Linxiang Yin, Hye Joung Choi and Bao Ting Zhu , PDIp Is a Major Intracellular Estrogen-Storage Protein That Modulates the Tissue Levels of Estrogen in the Pancreas , Biochem. J. , 2012 , Oct 1;447(1):115-23.
9. Xinmiao Fu, Pan Wang and Bao Ting Zhu , Characterization of the Estradiol-Binding Site Structure of Human Protein Disulfide Isomerase (PDI) , PLoS ONE , 2011 , 6(11):e27185. Epub 2011 Nov 3.
10. Fu XM, and Zhu BT , Human Pancreas-Specific Protein Disulfide Isomerase (PDIp) Can Function as a Chaperone Independently of Its Enzymatic Activity by Forming Stable Complexes with Denatured Substrate Proteins. , Biochem. J. , 2010 , 429:157-69 ,
11. Fu XM, Wang P, Zhu BT , Characterization of the Estradiol-Binding Site Structure of Human Pancreas-Specific Protein Disulfide Isomerase: Indispensable Role of the Hydrogen Bond between His278 and the Estradiol 3-Hydroxyl Group , Biochemistry , 2010 , 50:106-115
12. Fu XM and Zhu BT , Human pancreas-specific protein disulfide isomerase homolog (PDIp) is an intracellular estrogen-binding protein that modulates estrogen levels and actions in target cells , J Steroid Biochem Mol Biol. , 2009 , 115:20-29
13. Fu XM and Zhu BT , Human pancreas-specific protein disulfide isomerase homolog (PDIp) is redox-regulated through formation of an inter-subunit disulfide bond. , Arch Biochem Biophys , 2009 , 485:1-9
14. Fu XM, Dai X, Ding J, Zhu BT , Pancreas-specific protein disulfide isomerase has a cell type-specific expression in various mouse tissues and is absent in human pancreatic adenocarcinoma cells: implications for its functions , J Mol Histol. , 2009 , 40:189-99
15. Fu X, Wang P, Zhu BT , Protein disulfide isomerase is a multifunctional regulator of estrogenic status in target cells. , J Steroid Biochem Mol Biol. , 2008 , 112:127-37
16. Zhu J, Fu X, Koo YD, Zhu, JK, Jenney FEJr, Adams MW, Zhu Y, Shi H, Yun, DJ, Hasegawa PM and Bressan RA , , An enhancer mutant of Arabidopsis salt overly sensitive 3 mediates both ion homeostasis and the oxidative stress response. , Mol. Cell. Biol. , 2007 , 27:5214-5224. ,
17. Fu X, Jiao W and Chang Z , Phylogenetic and biochemical studies reveal a potential evolutionary origin of animal small heat shock proteins from bacterial class A , J Mol Evol. , 2006 , 62:257-266
18. Katiyar-Agarwal S, Zhu J, Kim K, Agarwal M, Fu X, Huang A and Zhu JK , The plasma membrane Na+/H+ antiporter SOS1 interacts with RCD1 and functions in oxidative stress tolerance in Arabidopsis , Proc. Natl. Acad. Sci. USA , 2006 , 103:18816-18821
19. Fu X, Zhang H, Zhang X, Cao Y, Jiao W, Liu C, Song Y, Abulimiti A and Chang Z , A dual role for the N-terminal region of Mycobacterium tuberculosis Hsp16.3 in self-oligomerization and binding denaturing substrate proteins. , J. Biol. Chem. , 2005 , 280:6337-6348
20. Fu X, Zhang X and Chang Z , 4,4'-dianilino-1,1'-binaphthyl-5,5'-sulfonate (bis-ANS), a novel molecule having chaperone-like activity. , Biochem. Biophys. Res. Commun. , 2005 , 329:1087-1093.
21. Zhang X, Fu X, Zhang H and Chang Z , chaperone-like activity of beta-casein. , Int. J. Biochem. Cell. Biol. , 2005 , 37:1232-1240. ,
22. Fu X and Chang Z , Temperature-dependent subunit exchange and chaperone-like activities of Hsp16.3, a small heat shock protein from Mycobacterium tuberculosis , Biochem. Biophy. Res. Commun. , 2004 , 316:291-299
23. Liu Y, Fu X, Shen J, Zhang H, Hong W and Chang Z , Periplasmic proteins of Escherichia coli are highly resistant to aggregation: revaluation for roles of molecular chaperones in periplasm. , Biochem. Biophy. Res. Commun. , 2004 , 316:795-801.
24. Abulimiti A*, Fu X*, Gu L, Feng X and Chang Z , Mycobacterium tuberculosis Hsp16.3 Nonamers are Assembled and Re-assembled via Trimer and Hexamer Intermediates. , J. Mol. Biol. , 2003 , 326:1013-1023. , * contributed equally
25. Fu X, Liu C, Liu Y, Feng X, Gu L, Chen X and Chang Z , , Small heat shock protein Hsp16.3 modulates its chaperone activity by adjusting the rate of oligomeric dissociation. , Biochem. Biophys. Res. Commun. , 2003 , 310: 412-420
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