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The Role of Protein Structure and Dynamics in the Inhibition of NF-kappaB by IkappaB Proteins


The NFκB signaling pathway is a central regulator of inflammatory and immune responses in virtually all human cell and tissue types, and aberrant signaling by NFκB has been implicated in a wide array of disease states including cancer, autoimmune diseases, and Alzheimer’s disease among others. Inhibition of NFκB by binding of IκB proteins represents the most robust regulatory mechanism for controlling the initiation and duration of the NFκB signaling event. NFκB and IκB both denote families of dimeric transcription factors and their inhibitor proteins, respectively. NFκB transcription factors self associate to form functionally active dimers which then bind in a specific manner to different IκB family members.

Here I present an extensive review of transcription factors and the NFκB pathway (Chapter I) to provide context for my work. I then describe a detailed analysis using hydrogen-deuterium exchange mass spectrometry (HDXMS) to probe the impact of IκBα binding on the internal dynamics of the p50/RelA NFκB heterodimer and demonstrate that long-range conformational changes induced by IκBα binding are of central importance to the inhibitory nature of the IκBα binding event (Chapter II).

Chapter III describes the first detailed biophysical analysis of the most recently discovered IκB protein, IκBε. I combined homology modeling and HDXMS to establish the presence of a seventh ankyrin repeat (AR) in IκBε and further provide a framework for utilizing HDXMS as a tool to complement homology modeling of proteins with no known structures. After identifying the seventh AR in IκBε, I performed the first comprehensive examination of IκBε’s ability to bind all NFκB dimers and the biophysical consequences on IκBε’s internal dynamics upon binding to its preferred NFκB dimers (Chapter IV). Finally, to further probe the interaction of IκBε with its preferred NFκB binding partners, I describe the impact of IκBε binding on the dynamics of the cRel heterodimers which are the NFκB proteins which bind IκBε with the highest affinity and discover the importance of entropic forces in driving these high affinity interactions (Chapter V).

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