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 #
2P01GM071862-06A1
Application #
8260170
Study Section
Special Emphasis Panel (ZRG1-BCMB-D (40))
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$302,230
Indirect Cost
$107,138
Name
University of California San Diego
Department
Type
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Trelle, Morten Beck; Ramsey, Kristen M; Lee, Taehyung C et al. (2016) Binding of NFκB Appears to Twist the Ankyrin Repeat Domain of IκBα. Biophys J 110:887-95
Xu, Jinjin; Zhou, Lei; Ji, Lei et al. (2016) The REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis. Nat Commun 7:10761
Dyson, H Jane (2016) Making Sense of Intrinsically Disordered Proteins. Biophys J 110:1013-6
Mukherjee, Sulakshana P; Borin, Brendan; Quintas, Pedro O et al. (2016) NMR characterization of a 72 kDa transcription factor using differential isotopic labeling. Protein Sci 25:597-604
Hsu, Che-Hsiung; Park, Sangho; Mortenson, David E et al. (2016) The Dependence of Carbohydrate-Aromatic Interaction Strengths on the Structure of the Carbohydrate. J Am Chem Soc 138:7636-48
Tsai, Min-Yeh; Zheng, Weihua; Balamurugan, D et al. (2016) Electrostatics, structure prediction, and the energy landscapes for protein folding and binding. Protein Sci 25:255-69
Mukherjee, Sulakshana P; Quintas, Pedro O; McNulty, Reginald et al. (2016) Structural characterization of the ternary complex that mediates termination of NF-κB signaling by IκBα. Proc Natl Acad Sci U S A 113:6212-7
Potoyan, Davit A; Zheng, Weihua; Komives, Elizabeth A et al. (2016) Molecular stripping in the NF-κB/IκB/DNA genetic regulatory network. Proc Natl Acad Sci U S A 113:110-5
Wolynes, Peter G (2015) Evolution, energy landscapes and the paradoxes of protein folding. Biochimie 119:218-30
Balasubramaniam, Deepa; Schiffer, Jamie; Parnell, Jonathan et al. (2015) How the ankyrin and SOCS box protein, ASB9, binds to creatine kinase. Biochemistry 54:1673-80

Showing the most recent 10 out of 90 publications