Lynne Regan

Lynne Regan's picture
Professor of Molecular Biophysics and Biochemistry and of Chemistry
266 Whitney Ave, New Haven, CT 06511-8902
203 432 9843

Professor of Chemistry
Member of Yale faculty since 1990

Research Protein Structure, Function, and Design We are interested in the fundamental question: How does a protein’s primary sequence specify its three dimensional structure? In addition, we are investigating the mechanisms by which proteins achieve the exquisite specificity and efficiency that are characteristic of protein-ligand interactions and enzymatic catalysis. Our research focuses upon small proteins, particularly four-helix bundle proteins, that are amenable to study by a variety of biophysical, biochemical and molecular biological techniques.

Designed Metal-Binding Proteins We have introduced novel metal-binding sites into two proteins: a designed four-helix bundle protein, a4 and the B1 domain of IgG-binding protein G. The metal-site designs are for both structural and catalytic tetrahedral Zn(II) sites. The structural sites enhance the stability of the proteins, whereas the catalytic sites aim to exploit the powerful nucleophilic activity of Zn(II)- bound water and to mimic natural enzymes such as carbonic anhydrase and carboxypeptidase. These studies allow us to delineate the features that are important for protein-Zn(II) interactions and have the potential to generate proteins with novel catalytic activities.

Rop (Rom), a Natural Four-Helix Bundle Protein Rop is a four-helix bundle protein whose role in vivo is to bind to a complex of two RNA molecules, in a key step in the regulation of replication of ColE1 plasmids. The crystal structure of Rop has been solved at 1.7 resolution and its NMR spectrum is completely assigned. These results facilitate a detailed structural characterization of the protein variants we create. We are using Rop as a model four-helix bundle protein in which to study helix-helix interactions by a systematic re-design of its hydrophobic core. Rop also provides a useful system in which to investigate the contribution of connecting loops to protein stability and folding. Finally, in conjunction with the Crothers laboratory, we are investigating the mechanism by which Rop recognizes its RNA substrate and the energetic contributions of the specific interactions involved.

A Model System to Study b-Sheet Formation. The factors that are important for a-helix formation are much better understood than those for b-sheet formation. This is largely because tractable model systems in which to study b-sheet formation have been lacking. We are using the B1 domain of Ig-binding protein G as an ideal model system in which to study b-sheet formation. We have determined both the intrinsic b-sheet forming propensities of the amino acids and the energetics of pair-wise interactions across two strands of a b-sheet. The results of these studies allow us to formulate the first guidelines for rational b-sheet design.


B.A. Oxford University, 1981
Ph.D. Massachusetts Institute of Technology, 1987
Visiting Scientist, E.I. du Pont de Nemours & Company, 1987-89
Visitor, Structural Studies Division, The Laboratory of Molecular Biology, MRC, Cambridge, U.K., 1989-90

Recent Publications

S.F. Marino & L. Regan. Secondary ligands enhance affinity at a designed metal-binding site. Chem. Biol. 1999, 6, 49-55.

A. Nagi, K.S. Anderson, & L. Regan, L. Using loop length variants to dissect the folding pathway of a four-helix bundle protein. J. Mol. Biol. 1999, 1, 257-265.

I. Ghosh, A.D. Hamilton, & L. Regan. Antiparallel leucine zipper-directed protein reassembly: application to the green fluorescent protein. J. Am. Chem. Soc.2000, 122, 5658-9.

J.S. Merkel & L. Regan. Modulating protein folding rates in vivo and in vitro by side-chain interactions between the parallel b strands of green fluorescent protein. J. Biol. Chem. 2000, 275, 29200-6.

M. Ramirez-Alvarado, J.S. Merkel, & L. Regan. A systematic exploration of the influence of the protein stability on amyloid fibril formation in vitro. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 8979-84.

Research Interests