Members of the two protein families, transcription factor NFKB and inhibitor kB, are functionally intertwined. Their close functional connectivity arises from their ability to regulate each other both through direct proteinprotein interactions and at the level of transcription. Through these regulatory events the 'IKB-NFKB module'plays decisive roles in various physiological outcomes, in particular, inflammatory and immune responses, and control of cell survival and proliferation. The NFKB family consists of several dimers that arise through combinatorial association of five related proteins: p50 (NFKB1);p52 (NFKB2);RelA (p65), cRel and RelB. The IKB family consists of three classical IKBS, Ixfia, -P and -e, which bind NFKB in a 1:1 stoichiometry (one kB complexed to one NFKB dimer), and IKBY and kB5, which consists of pi05 and pi 00 assembled into high molecular weight oligomers. In the current funding cycle we have demonstrated a distinct ubiquitinindependent degradation pathway for free IKBU, and we have characterized the nature of non-classical kBy and IKB6. In the next funding cycle, we will characterize the biochemical mechanism by which all three classical free kBs are degraded. In addition, we will determine the interaction specificity between classical IKBS and NFKB dimers, and test the hypothesis that IKBP and IKBS are responsible for stabilizing certain NFKB dimers, thus performing chaperone functions, and that they do so through NFKB-dimer-specific molecular interaction strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM071862-08
Application #
8627177
Study Section
Special Emphasis Panel (ZRG1-BCMB-D)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2014
Total Cost
$297,984
Indirect Cost
$105,736
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
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
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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