| NSF Org: |
MCB Division of Molecular and Cellular Biosciences |
| Recipient: |
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| Initial Amendment Date: | August 5, 1998 |
| Latest Amendment Date: | May 25, 2000 |
| Award Number: | 9808474 |
| Award Instrument: | Continuing Grant |
| Program Manager: |
Parag R. Chitnis
MCB Division of Molecular and Cellular Biosciences BIO Directorate for Biological Sciences |
| Start Date: | August 15, 1998 |
| End Date: | July 31, 2002 (Estimated) |
| Total Intended Award Amount: | $300,000.00 |
| Total Awarded Amount to Date: | $305,000.00 |
| Funds Obligated to Date: |
FY 1999 = $105,000.00 FY 2000 = $100,000.00 |
| History of Investigator: |
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| Recipient Sponsored Research Office: |
400 HARVEY MITCHELL PKWY S STE 300 COLLEGE STATION TX US 77845-4375 (979)862-6777 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
400 HARVEY MITCHELL PKY S STE 300 COLLEGE STATION TX US 77845-4375 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | MOLECULAR BIOCHEMISTRY |
| Primary Program Source: |
app-0198 app-0199 |
| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.074 |
ABSTRACT
HU MCB 9808474 1. Technical How proteins recognize other proteins is of fundamental importance in virtually every biological process. Leucine zippers, which form a variety of small alpha-helical oligomers, provide an ideal system to study the forces determining the stability and specificity of protein-protein interactions. This study builds on earlier genetic studies to examine how amino acid sequences determine the dimerization specificities of leucine zippers. Previously, mutant zippers with altered dimerization specificities were isolated with changes at the a, e, and g positions of the characteristic heptad repeat (abcdefg)n. Mutants with substitutions at the a positions fell into mutually exclusive classes and clear rules predicted their specificities. In contrast, the dimerization specificities of mutants altered at the e and g positions were complex and inconsistent with simple predictive models involving intersubunit ionic interactions. Two classes of questions will be addressed. First, how do the thermodynamic stabilities of homodimers and heterodimers determine the specificities of these mutant and wild-type zippers? Thermodynamic parameters for homodimeric and heterodimeric leucine zipper peptides will be measured by circular dichroism and fluorescence methods. Second, how do sequence patterns at the a, e, and g positions affect dimerization specificity? New mutants will be isolated using selections and screens for particular patterns of homodimer and heterodimer formation that were not found in earlier studies. The specificities of mutants will be are compared to naturally occurring leucine zippers, evaluated in a common assay. These data should provide a critical test of models and algorithms designed to predict dimerization specificity. 2. Non-technical A variety of small alpha-helical peptides is enriched in the amino acid leucine, and such a family of structures is hence named leucine zippers. These sequences pr ovide an ideal system to understand the forces determining the stability and specificity of protein-protein interactions, as many proteins dimerize by interacting through their leucine zippers. In this study, mutated sequences with changed dimerization specificities or with substitutions are compared, using circular dichroism and fluorescence methods. The questions to be addressed are: (1) how do the thermodynamic stabilities of homodimers and heterodimers determine the specificities of these mutant and wild-type zippers? and (2) how do sequence patterns at specific positions affect dimerization specificity? These results will provide a critical test of models and algorithms designed to predict dimerization specificity of proteins.
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