The NFKB signaling system mediates both transient inflammatory responses that involve highly dynamic control of transcription, and longer-term immunological responses and development that involve precise dose response control mechanisms (14, 29). All are critical to human health, as demonstrated by NFKB involvement in inflammatory disease and in lymphocytic malignancies (37). These fundamentally different functions are achieved by the interplay of distinct family members of transcriptional activators and inhibitor proteins, whose biophysical properties determine their half-life control, interaction specificity, and dynamic and dose response behavior. A predictive understanding of the functioning of the NFKB signaling system in physiology and pathology remains unrealized, primarily due to a lack of information about the fundamental regulatory mechanisms and associated molecular specificities of key NFKB and IKB family members, and our inability to integrate diverse information and link it to specific physiological functions of cells and animal model systems. The present proposal aims to address these deficiencies. It complements the other projects of the Programand involves highly integrated studies, leveraging the molecular biophysical insights about protein folding, degradation and molecular interaction, to develop a predictive understanding of cellular signaling processes in inflammation and immune responses. This is achieved through the integrated approaches of biochemistry, mathematical modeling, cell biology, and animal physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
4P01GM071862-10
Application #
9024567
Study Section
Special Emphasis Panel (ZRG1)
Project Start
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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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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