FOLDING AND BINDING OF IKBA/NF-KB COMPLEXES

University Of California, San Diego, La Jolla CA

Investigators

Linked publications & trials

Abstract

The NF-KB/lKBalpha system is an essential cell signaling system and is representative of a family of protein-protein[unreadable] interactions in the cell. The function of this system provides a challenge to the main structure-function[unreadable] paradigm in biophysics because parts of both partners are incompletely structured when the[unreadable] molecules are isolated. Thus there are major implications for many areas of proteomics, which also involve[unreadable] natively unfolded proteins. Specific recognition of IKBalpha by NF-KB involves collaborative folding and[unreadable] binding between the two proteins. We will investigate computationally the kinetics of this process, because[unreadable] this collaborative folding/binding event may be an example of the proposed "fly-casting mechanism"[unreadable] previously suggested by us as a possible reason for utilization of unfolded proteins in biological systems.[unreadable] These studies will combine energy landscape theory with simulations using a variety of model energy[unreadable] functions. This system is a particularly auspicious choice for such a study because a very extensive model of[unreadable] the in vivo kinetics has already been established and tested in the Hoffmann laboratory. Thus the evolutionary[unreadable] and functional significance of "fly-casting" can be assessed. Our theoretical predictions will be tested by[unreadable] laboratory investigations of the Ghosh, Komives and Dyson groups. The collaborative folding/binding found[unreadable] here raises more general issues concerned with experimental and theoretical characterization of the structure[unreadable] of proteins with dispersed ensembles of structures. Developing computer algorithms for dealing with this[unreadable] circumstance, based on replica methods and energy landscape theories, is another focus of our theoretical[unreadable] work. Developing approaches to predict binding modes for such floppy proteins using sequence information[unreadable] alone is another goal. Finally the basic biophysics that drives the association of partially folded partners will[unreadable] be addressed using the simulation models we generate. Studying the underlying forces in molecular detail[unreadable] may give insight into the specificity patterns exhibited by this family of proteins, which participate in many[unreadable] different signaling events relevant to physiological responses. The NF-KB/lKBalpha system has been implicated[unreadable] in several diseases ranging from osteoporosis to septic shock. Controlling folding/binding in this system may[unreadable] provide a new strategy for drug intervention, although our emphasis is on the basic science of the problem.