DESCRIPTION (provided by applicant): WD repeats are ubiquitous 40 amino acids sequence repeats found in hundreds of proteins mediating signal transduction, mRNA splicing, cell cycle regulation, vesicular trafficking, developmental regulation and numerous other physiologically relevant processes involving protein-protein interactions. Accurate modeling and prediction of these proteins' functions demand a complete understanding of how they fold. Based upon the crystal structure of the b subunit of the G protein transducin which has seven repeats and folds into a seven-bladed propeller motif, it has been predicted that the number of blades a particular WD protein has is dictated by the number of WD repeats it possesses, leading to proteins with a variable number of blades. The recent structure of Bub3p, a mitotic checkpoint protein, brings this hypothesis into question. Structures of these proteins will establish a standard model for WD repeat protein structure, one that will be applicable to the hundreds of known sequences as well as the large numbers which will presumably be discovered through ongoing genomic sequencing efforts. In light of the Bub3p structure, a protein believed to contain only four repeats based upon the sequence but found to contain seven in the structure, a hypothesis can be formed that virtually all WD proteins fold into a similar, stable, seven-bladed core structure. Additionally, it also seems likely that these proteins would bind their partner proteins in a similar manner. Preliminary results support this notion. Structural and functional experiments will be conducted to better understand WD repeat proteins and their interactions in general terms 1) the determination of at least four WD protein structures with "irregular" numbers of repeats predicted by sequence to investigate the possibility of a standard fold and 2) structural, genetic and biochemical characterization of these proteins' interactions with binding partners will determine whether the protein-protein interactions follow a common pattern.
|Effective start/end date||7/1/02 → 6/30/07|
- National Institutes of Health: $236,209.00
- National Institutes of Health: $236,109.00
- National Institutes of Health: $244,023.00
- National Institutes of Health: $224,385.00
- Biochemistry, Genetics and Molecular Biology(all)