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Molecular and Cellular Biology

Houston, Texas

Image 1: Ovulated mouse cumulus cell oocyte complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.; Image 2: By Yi LI, Ph.D.; Image 3: Mouse oocyte at meiosis I immunostained  for tubulin (red) phosphop38MAPK (green) and DNA (blue). By JoAnne Richards,  Ph.D.;  Image 4: Expanded cumulus cell ooctye ocmplex  immunostained for hyaluronan (red), TSG6 (green) and DAN (blue). By JoAnne  Richards, Ph.D.;  Image 5: Epithelial cells taken from a mouse  mammary gland were cultured in a dish and transduced with a retrovirus  expressing two genes. The green staining shows green fluorescent protein and the red  staining shows progesterone receptor expression. The nucleus of each cell is  stained blue. Photomicrograph taken at 200X magnification.  By Sandra L. Grimm,  Ph.D.; Image 6: Ovarian vasculature (red) is excluded from the granulosa cells (blue) within growing follicles (round structures); Image 7:  Ovulated mouse cumulus cell oocyte  complex immunostained for matrix proteins hyaluronan and versican. By JoAnne Richards, Ph.D.
Department of Molecular and Cellular Biology
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Francis T.F. Tsai, D.Phil.

Francis T.F. Tsai, Ph.D. photoProfessor
Departments of Biochemistry and Molecular Biology and Molecular and Cellular Biology

Education

D.Phil.: University of Oxford, Oxford, United Kingdom
Postdoctoral training: Yale University/HHMI, New Haven

Research Interest

Structural Biochemistry of Molecular Chaperones and Transcription Factor Assemblies
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 GroEL (Hsp60), DnaK (Hsp70) and HtpG (Hsp90), 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.

ClpB (Hsp104) is a 600-kDa ATP-dependent molecular machine that, together with the cognate DnaK 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 hydrolysis into mechanical work in order to disaggregate previously aggregated proteins. To this end, we have solved the 3-Å resolution crystal 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; Mol. Cell 2007).

If our molecular understanding of ClpB is correct, we can exploit this information to design new machines with novel functional properties. In collaboration with Professor Bernd Bukau’s lab at the University of Heidelberg in Germany, we have engineered a ClpB variant (BAP) that, unlike ClpB wild-type, can associate with a chambered protease (ClpP) in an ATP-dependent manner. While ClpB and BAP share the ability to disaggregate proteins, BAP (but not ClpB) functions as a novel disaggregating-degrading machine in the presence of ClpP. Using BAP, we demonstrated that substrates must translocate through the central pore of the ClpB hexamer and, perhaps more importantly, that thermotolerance requires the refolding of aggregated proteins (Weibezahn et al. Cell 2004; Haslberger et al. Mol. Cell 2007).

Contact Information

Baylor College of Medicine
One Baylor Plaza, Anderson 315B
Houston, TX 77030

Phone: 713-798-8668
E-mail: ftsai@bcm.edu
Lab Web Site: http://www.bcm.edu/labs/tsai/

Selected Publications

  1. Biter AB, Lee S, Sung N and Tsai FTF. (2012). Structural Basis for Intersubunit Signaling in a Protein Disaggregating Machine, Proceedings of the National Academy of Sciences USA. In Press.
  2. Biter AB, Lee J, Sung N, Tsai FTF and Lee S. (2012). Functional Analysis of Conserved Cis- and Trans-elements in the Hsp104 Protein Disaggregating Machine, J. Struct. Biol. In Press. PMID: 22634726.
  3. Sielaff B, Lee KS and Tsai FTF. (2011). Structural and Functional Conservation of Mycobacterium tuberculosis GroEL Paralogs Suggests that GroEL1 is a Chaperonin, J. Mol. Biol. 405:831-839. PMID: 21094166.
  4. Lee S, Sielaff B, Lee J and Tsai FTF. (2010). CryoEM Structure of Hsp104 and Its Mechanistic Implication for Protein Disaggregation, Proceedings of the National Academy of Sciences USA, 107:8135-8140. PMID: 20404203.
  5. Augustin S, Gerdes F, Lee S, Tsai FTF, Langer T and Tatsuta T. (2009). An Intersubunit Signaling Network Coordinates ATP Hydrolysis by m-AAA Proteases, Mol. Cell 35:574-585. PMID: 19748354.
  6. Lee S, Choi J-M and Tsai FTF. (2007). Visualizing the ATPase Cycle in a Protein Disaggregating Machine: Structural Basis for Substrate Binding by ClpB, Molecular Cell, 25:261-271. PMID: 17244533.
  7. Rees I, Lee S, Kim H and Tsai FTF. (2006). The E3 Ubiquitin Ligase CHIP Binds the Androgen Receptor in a Phosphorylation-dependent Manner, Biochimica et Biophysica Acta, 1764:1073-1079. PMID: 16725394.
  8. Zhang J, Simisky J, Tsai FTF and Geller DS. (2005). A Critical Role of Helix3-helix 5 Interaction in Steroid Hormone Receptor Function, Proceedings of the National Academy of Sciences USA, 102:2707-2712. PMID: 15710879.
  9. Lee S, Sowa ME, Watanabe Y-H, Sigler PB, Chiu W, Yoshida M and Tsai FTF. (2003). The Structure of ClpB: a Molecular Chaperone that Rescues Proteins from an Aggregated State, Cell, 115:229-240. PMID: 14567920.
  10. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FTF, Sigler PB and Lifton RP. (2000). Activating Mineralocorticoid Receptor Mutation in Hypertension Exacerbated by Pregnancy, Science, 289:119-123. PMID: 10884226.

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