Laura Romberg

The increasing prevalence of drug-resistant bacteria has resulted in searches for new antibiotics. Penicillin inhibits bacterial elongation, but cell division is another potential target that is now being explored. A protein called FtsZ is essential for bacterial cell division and may make a good antibiotic target; it is present in nearly all bacterial species but is absent in humans. As a result, inhibiting FtsZ function could prevent bacteria from dividing without causing side effects due to interactions with human proteins.

FtsZ is a distant homolog of eukaryotic tubulin and polymerizes to form part of the bacterial cytoskeleton. Like the musculoskeletal system of our own bodies, a cell's cytoskeleton determines its shape and can produce force. However, unlike the bones in a skeleton, the structures in the cytoskeleton are transient. The cytoskeleton as a whole is maintained through continual, carefully balanced polymer assembly and disassembly. Understanding FtsZ's polymer dynamics will aid the development of drugs that can disrupt FtsZ structures and thereby prevent cell division.

In cells, FtsZ assembles into a ring at the future site of cell division. This ring is highly dynamic and can rapidly assemble, relocalize, constrict, and disassemble. Ring dynamics are due to the reversibility of FtsZ polymerization; like microtubules, FtsZ polymers assemble in the presence of GTP but tend to curve and disassemble after the GTP has been hydrolyzed.

It is unknown whether FtsZ exhibits the complex, cooperative behaviors of tubulin, including 1) nucleated assembly: the establishment of new polymers is less favorable than growth from pre-established polymers, and 2) dynamic instability: at steady state, individual polymers undergo abrupt transitions between steady growth and rapid shrinkage. My lab is addressing two major questions:1) At what level of assembly does cooperative polymerization emerge? 2) How is FtsZ polymerization promoted or inhibited by its interactions with other proteins?

1. *Miraldi, E., Thomas, P., and Romberg, L. 2008. Allosteric Models for Cooperative Polymerization of Linear Polymers. Biophysical Journal 95: 2470-2486. *undergraduate co-author

2. Margalit D.N., Romberg L., Mets R.B., Hebert A.M., Mitchison T.J., Kirschner M.W., and D. RayChaudhuri. 2004. Targeting cell division: small-molecule inhibitors of FtsZ GTPase perturb cytokinetic ring assembly and induce bacterial lethality. Proceedings of the National Academy of Sciences USA. 101(32):11821-6.

3. Romberg, L. and T.J. Mitchison. 2004. Rate-Limiting Guanosine 5'-Triphosphate Hydrolysis during Nucleotide Turnover by FtsZ, a Prokaryotic Tubulin Homologue Involved in Bacterial Cell Division. Biochemistry 43: 282-8.

4. Romberg, L., and P.A. Levin. 2003. Assembly dynamics of the bacterial cell division protein FtsZ: Poised at the edge of stability. Annual Review of Microbiology 57: 125-54.

5. Romberg, L., M. Simon, and H.P. Erickson. 2001. Polymerization of FtsZ, a bacterial homolog of tubulin - Is assembly cooperative? Journal of Biological Chemistry 276: 11743-11753.

6. Romberg, L., D.W. Pierce, and R.D. Vale. 1998. Role of the kinesin neck region in processive microtubule-based motility. Journal of Cell Biology 140: 1407-16.

7. Vale, R.D., T. Funatsu, D.W. Pierce, L. Romberg, Y. Harada, and T. Yanagida. 1996. Direct observation of single kinesins molecules moving along microtubules. Nature 380: 451-453.

8. Romberg, L., and R.D. Vale. 1993. Chemomechanical cycle of kinesin differs from that of myosin. Nature 361: 168-170.

9. Suter, B., Romberg, L.M., and R. Steward. 1989. Bicaudal-D, a Drosophila gene involved in developmental asymmetry: localized transcript accumulation in ovaries and sequence similarity to myosin heavy chain tail domains. Genes and Development 12A: 1957-68.