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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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University of California San Diego
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Wolynes, Peter G (2015) Evolution, energy landscapes and the paradoxes of protein folding. Biochimie 119:218-30
Potoyan, Davit A; Wolynes, Peter G (2014) On the dephasing of genetic oscillators. Proc Natl Acad Sci U S A 111:2391-6
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Alves, Bryce N; Tsui, Rachel; Almaden, Jonathan et al. (2014) I?B? is a key regulator of B cell expansion by providing negative feedback on cRel and RelA in a stimulus-specific manner. J Immunol 192:3121-32
Ferreiro, Diego U; Komives, Elizabeth A; Wolynes, Peter G (2014) Frustration in biomolecules. Q Rev Biophys 47:285-363
Kim, Bobby L; Schafer, Nicholas P; Wolynes, Peter G (2014) Predictive energy landscapes for folding ?-helical transmembrane proteins. Proc Natl Acad Sci U S A 111:11031-6
Cervantes, Carla F; Handley, Lindsey D; Sue, Shih-Che et al. (2013) Long-range effects and functional consequences of stabilizing mutations in the ankyrin repeat domain of IýýBýý. J Mol Biol 425:902-13

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