DESCRIPTION (provided by applicant): The ability of proteins to change structure impacts upon many biological processes, including the evolution of new folds and functions from ancestral precursors, the regulation of allosteric systems, and the development of amyloid diseases. The long-term goal of this work is to understand how large-scale structural change is promoted or prevented by changes in amino-acid sequence. For this purpose, I have chosen as a model system the cro family of bacteriophage DNA-binding proteins. Members of this family have related sequences but very different folds. Lambda cro has a dimeric alpha+beta fold, while preliminary results show that P22 cro has a monomeric all-alpha fold consisting of five helices. The lambda cro variant A33W/F58D appears to represent still a third, intermediate type of structure, a monomeric alpha+beta fold. The sequences of these proteins have been aligned, and are homologous even in the region where their structures are most different. I intend to use lambda cro, P22 cro and lambda cro A33W/F58D as a representative set of aligned sequences encoding three distinct structures. Using these approaches, I will a) elucidate the key sequence determinants which distinguish the all-alpha and alpha+beta folds in cro proteins, b) elucidate the sequence determinants of strong dimerization in lambda cro, and characterize the structure of intermediate monomeric alpha+beta variants, c) design structurally ambivalent sequences which are compatible with both five-helix and alpha+beta folds. In addition, I will characterize additional proteins in this family to expand the system beyond the P22/lambda model.
|Effective start/end date||8/1/03 → 11/30/13|
- National Institutes of Health: $244,769.00
- National Institutes of Health: $249,899.00
- National Institutes of Health: $308,704.00
- National Institutes of Health: $24,953.00
- National Institutes of Health: $308,881.00
- National Institutes of Health: $286,945.00
- National Institutes of Health: $249,830.00
- National Institutes of Health: $311,597.00
- National Institutes of Health: $207,087.00
- National Institutes of Health: $309,305.00
- Biochemistry, Genetics and Molecular Biology(all)
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