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Francis Tsai Baylor College of Medicine Department: Biochemistry and Molecular Biology Address: One Baylor Plaza, MS: BCM125, Room 315B Houston, TX 77030 Phone: (713) 798-8668 Fax: (713) 796-9438 Email: ftsai@bcm.tmc.edu Web: www.bcm.edu/labs/tsai/

Education

B.Sc. Chemistry & Biochemistry, Imperial College of Science, Technology and Medicine (Univ. of London) (1993)
D.Phil. Biochemistry, Univ. of Oxford (1997)
Wellcome Trust Postdoctoral Fellow, Yale University/HHMI (Sigler Lab; 1996-2000)

Honors

Norman Hackerman Award in Chemical Research, 2008
Research Scholar Award from the American Cancer Society, 2008-2011
Scientist Development Award from the American Heart Association, 2001-2004
Junior Faculty Award from the Gillson Longenbaugh Foundation, 2001
Wellcome Trust Postdoctoral Fellow, 1997-1998
NIH Postdoctoral Fellowship (declined in lieu of Wellcome Trust Fellowship)
Associateship of the Royal College of Science, 1993

Research Topic

Structure and Function of Macromolecular Complexes and Supramolecular Assemblies

Research Description

Proteins must fold correctly in order to attain biological function. Concurrently, protein misfolding and aggregation are primary contributors to many human neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and transmissible spongiform encephalopathy (TSE), better known as the human form of "Mad Cow Disease". Molecular chaperones, such as Hsp60 (GroEL), Hsp70 (DnaK) and Hsp90 (HtpG), assist protein folding by either promoting the "forward" folding or preventing the aggregation of proteins. However, once aggregates have formed, these molecular chaperones cannot facilitate protein disaggregation.

Hsp104 (ClpB) is a 600 kDa ATP-dependent molecular machine that, together with the cognate Hsp70 chaperone system, has the remarkable ability to rescue stress-damaged proteins from a previously aggregated state. My lab is interested in understanding how ClpB converts the energy derived from ATP binding and/or hydrolysis into mechanical work in order to disaggregate previously aggregated proteins. To this end, we have solved the atomic structure of ClpB using X-ray crystallography, and the structure of the functional ClpB assembly using electron cryo-microscopy and single-particle reconstruction techniques (Lee et al. Cell 2003). More recently, we have determined the hexameric structures of ClpB in different nucleotide-bound states, which revealed the conformational changes that occur during ATP binding and hydrolysis (Lee et al. Mol. Cell 2007). Taken together, our structure provides the much needed stereochemical framework to further investigate the mechanism of protein disaggregation (e.g. Weibezahn et al. Cell 2004; Haslberger et al. Mol. Cell 2007).

In recognition of our structural and mechanistic studies of ClpB, Dr. Tsai was awarded The Welch Foundation's 2008 Norman Hackerman Award in Chemical Research. This prestigious award is given to encourage and recognize young chemical scientists in Texas for their past research endeavors, and to serve as encouragement to those who are embarking on careers dedicated to increasing our fundamental understanding of chemistry.

Enquiries to pursue your Ph.D. thesis or postdoctoral training with us are welcome.

Selected Publications

• Lee S and Tsai FTF. Crystallization and Preliminary X-ray Crystallographic Analysis of a 40 kDa N-terminal Fragment of the Yeast Prion-remodeling Factor Hsp104. Acta Crystallogr. F 63:784-786 (2007).
• Lee S, Choi JM and Tsai FTF. Visualizing the ATPase Cycle in a Protein Disaggregating Machine: Structural Basis for Substrate Binding by ClpB. Mol. Cell 25:261-271 (2007).
• Haslberger T, Weibezahn J, Zahn R, Lee S, Tsai FTF, Bukau B and Mogk A. M Domains Couple the ClpB Threading Motor with the DnaK Chaperone Activity. Mol. Cell 25:247-260 (2007).
• Zhang J, Tsai FTF and Geller DS. Differential Interaction of RU486 with the Progesterone and Glucocorticoid Receptors. J. Mol. Endocrinol. 37:163-173 (2006).
• Rees I, Lee S, Kim H and Tsai FTF. The E3 Ubiquitin Ligase CHIP Binds the Androgen Receptor in a Phosphorylation-dependent Manner. Biochem. Biophys. Acta. 1764:1073-1079 (2006).
• Lee S and Tsai FTF. Molecular Chaperones in Protein Quality Control. J. Biochem. Mol. Biol. 38:259-265 (2005).
• Zhang J, Simisky J, Tsai FTF and Geller DS. A critical role of helix3-helix 5 interaction in steroid hormone receptor function. Proc. Natl. Acad. Sci. USA 102:2707-2712 (2005).
• Weibezahn J, Tessarz P, Schlieker C, Zahn R, Maglica Z, Lee S, Zentgraf H, Weber-Ban E, Dougan D, Tsai FTF, Mogk A and Bukau B. Thermotolerance requires refolding of aggregated proteins by substrate translocation through the central pore of ClpB. Cell 119:653-665 (2004).
• Lee S, Sowa ME, Choi JM and Tsai FTF. The ClpB/Hsp104 molecular chaperone a protein disaggregating machine. J. Struct. Biol. 146:99-105 (2004).
• Lee S, Sowa ME, Watanabe Y, Sigler PB, Chiu W, Yoshida M and Tsai FTF. The structure of ClpB: a molecular chaperone that rescues proteins from an aggregated state. Cell 115:229-240 (2003).
• Lee S, Hisayoshi M, Yoshida M and Tsai FTF. Crystallization and preliminary X-ray crystallographic analysis of the Hsp100 chaperone ClpB from Thermus thermophilus. Acta Crystallogr. D 59:2334-2336 (2003).
• Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FTF, Sigler PB and Lifton RP. Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy. Science 289:119-123 (2000).
• Tsai FTF and Sigler PB. Structural Basis of Preinitiation Complex Assembly on Human Pol II Promoters. EMBO J. 19:25-36 (2000).
• Tsai FTF, Littlefield O, Kosa PF, Cox JM, Schepartz A and Sigler PB. Polarity of Transcription on Pol II and Archaeal Promoters: Where is the "One-way Sign" and How is it Read? Cold Spring Harb. Symp. Quant. Biol. 63:53-61 (1998).
• Tsai FTF, Singh OMP, Skarzynski T, Wonacot AJ, Weston S, Tucker A, Pauptit RA, Breeze AL, Poyser JP, O'Brien R, Ladbury JE and Wigley DB. The high-resolution crystal structure of a 24-kDa gyrase B fragment from E. coli complexed with one of the most potent coumarin inhibitors, clorobiocin. Proteins 28:41-52 (1997).
• Tsai FTF, Subramanya HS, Brannigan JA, Wilkinson AJ and Wigley DB. Crystallization and Preliminary Crystallographic Analysis of the DNA Gyrase B Protein from B. steraothermophilus. Acta Crystallogr. D 52:1216-1218 (1996).

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Last edited on: August 20, 2009