The School of Molecular and Cellular Biology at the University of Illinois at Urbana-Champaign

Physiological balance is maintained, in part, through the rapid and well-timed assembly and disassembly of biological complexes. The dynamic interplay between select factors, which includes but is not limited to proteins and nucleic acids, facilitates an efficient cellular communication network. In general, pathways are driven forward through cooperative interactions, thereby providing important features for these systems—rapid and robust action with limited energy input. However, within multi-step systems cooperative stable assemblies may have a drawback since each complex would be recalcitrant to dissociation. Hence, transitions between functional complexes or termination of action would be slow unless catalyzed. Yet, the possible cellular actions that promote disassembly events are not well understood. The primary focus of our laboratory is to identify and to understand the cellular components that mediate the dynamics of transcription and telomere protein complexes.

Recent cell biology studies have revealed the dynamic nature of diverse nuclear complexes in vivo despite the static behavior of comparable structures in vitro (Misteli, 2001a; Bubulya and Spector, 2004; Hager et al., 2004). For example, the glucocorticoid receptor transiently associates (t 1/2 ~2 sec) with its response element at a regulated promoter in vivo (McNally et al., 2000; Stavreva et al., 2004); yet, binding to the same response element in vitro is rather prolonged (t 1/2 ~100 min) (Perlmann et al., 1990). While the kinetics of telomerase-telomere interactions have not been determined in vivo, telomerase certainly forms long-lived DNA complexes in vitro yet can rapidly elongate shortened telomeres within a limited period of late S-phase suggesting that the enzyme is capable of dynamic action in vivo (Prescott and Blackburn, 1997; Teixeira et al., 2004). Perhaps of note, the telomere-binding proteins TRF1 and TRF2 can have rapid telomere associations on the second time scale in vivo (Mattern et al., 2004); the kinetics of TRF2 vary in a manner consistent with its dual role in telomere length regulation and in chromosome end protection. Hence, both regulated promoters and telomeres may be comprised of a dynamic protein environment that would facilitate rapid transitions between functional states (e.g., capping to extension complexes) and promote efficient telomerase cycling during telomere elongation.

To achieve the rapid protein kinetics we suggest that the p23/Sba1p molecular chaperone fosters a dynamic action. In short, we suggest that transcription and telomere protein associations are driven forward by high affinity interactions between low abundant functional components (e.g., telomere-binding proteins such as telomerase, Cdc13p and Est1p) and that these complexes are disengaged through lower affinity interactions between key components (e.g., receptor or telomerase) and the abundant molecular chaperones. Thus, the molecular chaperones help create a dynamic environment without interfering with the functional activities required to perform a set function. Together these protein-protein interactions would create and maintain protein complexes governed by the principles of self-organization. Self-organization is a theoretical model used to describe the formation of macromolecular structures in which the involved components interact dynamically to determine the architectural and functional features of a system; in contrast, self-assembly assumes an equilibrium state between the involved components and a final static state (Prigogine and Nicolis, 1971; Misteli, 2001). While it is plausible that certain biological complexes follow the conventions of self-assembly, we suggest that in the presence of the appropriate factor(s) (e.g., molecular chaperones such as p23, Hsp90, Hsp70 or the 19S proteasome particle) most protein-containing structures will become dynamic and therefore will maintain structure and function through self-organizing principles.