The overall goal of the proposed work is to provide a quantitative biophysical description of the protein folding and binding kinetics and thermodynamics of members of the kB family as they interact with members of the NFKB family. Integration with the Wolynes project will correlate theory and experiment to develop a deeper understanding of how the protein structure determines its biophysical properties. Integration with the Dyson project will cross the time-scale boundaries from NMR time scale dynamics to longer time scales probed by H/D exchange and smFRET. Integration with the Hoffmann and Ghosh projects will provide a link between biophysical properties and function. A focus of the project is the intrinsic disorder of iKBa AR5-AR6-C-terminal EST-containing region and its role in establishing functional control of NFKB signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM071862-07
Application #
8459437
Study Section
Special Emphasis Panel (ZRG1-BCMB-D)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
7
Fiscal Year
2013
Total Cost
$351,701
Indirect Cost
$113,022
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ferreiro, Diego U; Komives, Elizabeth A; Wolynes, Peter G (2018) Frustration, function and folding. Curr Opin Struct Biol 48:68-73
Narang, Dominic; Chen, Wei; Ricci, Clarisse G et al. (2018) RelA-Containing NF?B Dimers Have Strikingly Different DNA-Binding Cavities in the Absence of DNA. J Mol Biol 430:1510-1520
Wang, Zhipeng; Potoyan, Davit A; Wolynes, Peter G (2018) Modeling the therapeutic efficacy of NF?B synthetic decoy oligodeoxynucleotides (ODNs). BMC Syst Biol 12:4
Ramsey, Kristen M; Narang, Dominic; Komives, Elizabeth A (2018) Prediction of the presence of a seventh ankyrin repeat in I?B? from homology modeling combined with hydrogen-deuterium exchange mass spectrometry (HDX-MS). Protein Sci 27:1624-1635
Wang, Zhipeng; Potoyan, Davit A; Wolynes, Peter G (2018) Stochastic resonances in a distributed genetic broadcasting system: the NF?B/I?B paradigm. J R Soc Interface 15:
Ramirez-Sarmiento, Cesar A; Komives, Elizabeth A (2018) Hydrogen-deuterium exchange mass spectrometry reveals folding and allostery in protein-protein interactions. Methods 144:43-52
Dembinski, Holly E; Wismer, Kevin; Vargas, Jesse D et al. (2017) Functional importance of stripping in NF?B signaling revealed by a stripping-impaired I?B? mutant. Proc Natl Acad Sci U S A 114:1916-1921
Potoyan, Davit A; Bueno, Carlos; Zheng, Weihua et al. (2017) Resolving the NF?B Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors. J Am Chem Soc 139:18558-18566
Potoyan, Davit A; Wolynes, Peter G (2017) Stochastic dynamics of genetic broadcasting networks. Phys Rev E 96:052305
Ramsey, Kristen M; Dembinski, Holly E; Chen, Wei et al. (2017) DNA and I?B? Both Induce Long-Range Conformational Changes in NF?B. J Mol Biol 429:999-1008

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