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Research

Summary

My laboratory uses a variety of structural biology and bioinformatics methods to gain fundamental knowledge of proteins and protein/DNA interactions. The current focus is analysis of transcription activation by CAP. Studies have also included analyses of trp repressor and outer surface antigens of Lyme borrelia, described below.
I am also working with the RCSB PDB to develop improved representations of large macromolecular assemblies.

CAP

At promoters such as lac and gal, the E. coli catabolite activator protein (CAP) recruits RNA polymerase to promoter DNA. Our aim is to define the precise molecular interactions involved in transcription activation by CAP. At right is our current model of class I CAP-dependent transcription activation. For more
information, see our review in Current Opinion in Structural Biology, and
PDB Molecule of the Month, Dec. 2003.
Our work on CAP is funded by NIGMS

trp Repressor

The E. coli trp repressor is a ligand-activated DNA-binding protein that prevents expression of genes for tryptophan synthesis and import when L-tryptophan is plentiful. Probably one of the best biochemically and structurally studied proteins of its type, recent structural studies are providing new insights into folding and activity.

A particularly exciting discovery we have made is that the protein crystallizes in an extended domain-swapped lattice in aqueous alcohols. Above, trp repressor is shown in its dimeric state (left) and its domain-swapped state (right). The helix-turn-helix DNA binding motif is highlighted in green.

Spirochete Surface Proteins

Another research interest has been the major outer surface proteins of the Lyme disease spirochete, Borrelia burgdorferi, and related Borrelia species, to understand how these proteins participate in immune evasion and pathogenicity.

Outer surface protein A (OspA) of B. burgdorferi is the basis for the first FDA approved vaccine to protect humans against Lyme Disease. Results of our structural studies on OspA are currently being used to aid in design of a second-generation vaccine. Outer surface protein C is another potential second generation vaccine. Click here for a review (pdf). We are continuing to investigate structural and chemical basis for altered organ target preference that results from sequence changes in the variable small membrane protein (Vsp) of the relapsing fever spirochete B. turicatae.

The animation at right shows models for native lipidated OspA and OspC based on crystal structures (OspA isasymmetric, OspC is a symmetric dimer)

1. Lawson, C.L., Dutta, S., Westbrook, J.D., Henrick, K. & Berman, H.M. Representation of Viruses in the Remediated PDB archive. Acta Cryst D 64:874-882 (2008).


2. Napoli, A.A., Lawson, C.L., Ebright, R.H. & Berman, H.M. Indirect readout of DNA sequence at the primary-kink site in the CAP-DNA complex: recognition of pyrimidine-purine and purine-purine steps. J Mol Biol. 357:173-83 (2006).


3. Lawson, C.L., Yung, B.H., Barbour, A.G. and Zückert, W.R. Crystal structure of neurotropism-associated variable surface protein 1 (Vsp1) of Borrelia turicatae. J Bacteriol 188:4522-30 (2006).


4. C. Lawson, B. Benoff, T. Berger, H. Berman, J. Carey E. coli trp repressor forms a domain-swapped array in aqueous alcohol. Structure 12(6):1099-108 (2004)


5. Lawson, C.L., Swigon, D., Murakami, K., Darst, S., Berman, H.M., Ebright, R.H. Catabolite Activator Protein: DNA bending and transcription activation. Current Opinion in Structural Biology 14, 10-20 (2004).


6. Daniels, BV, Myles, DAA, Forsyth, VT, and Lawson, CL. Crystals of trp repressor suitable for high resolution neutron Laue diffraction studies. Acta Cryst. D59, 136-138 (2003).Full Text PDF


7. W. Ding, X. Huang, X. Yang, J. J. Dunn, B. J. Luft, S. Koide, and C. L. Lawson (2000) Structural Identification of a Key Protective B-cell Epitope in Lyme Disease Antigen OspA. Journal of Molecular Biology (302) 1153-1164.1FJ1


8. Li H, Dunn JJ, Luft BJ, Lawson CL. (1997) Crystal structure of Lyme disease antigen outer surface protein A complexed with an Fab.Proc Natl Acad Sci U S A. (94) 3584-3589.1OSP