Graduation Semester and Year
Summer 2026
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Jongyun Heo
Second Advisor
Byung Ran So
Third Advisor
Subhrangsu Mandal
Fourth Advisor
Kayunta Johnson-Winters
Abstract
Enzyme regulation is essential for the coordination of normal cellular functions and is inherently dynamical, as living systems must constantly sense and respond to changing external and internal conditions. Typically, steady state kinetic models have been employed to study the ligand concentration-dependent kinetic features of enzymes. Despite the advances made with classical enzyme kinetics, traditional ligand-dependent kinetic studies are unable to adequately characterize many enzymes, particularly those with complex, time-dependent regulatory mechanisms. This work develops the concept of autoactivation, a time-dependent kinetic phenomenon, which can be viewed as a subtype of autocatalysis. In autoactivation, positive feedback results in increased enzymatic activity as a function of time, leading to the observation of an accelerating reaction rate. In some cases, autoactivation can result in temporal cooperativity. This is an extension on the traditional view of equilibrium cooperativity. Autoactivation is important in fundamental processes including enzymatic regulation, cell signaling, metabolism, cell defense, and more. Additionally, autoactivation provides a source of nonlinearity, a necessary component for emergent complexity in living systems.
In the case of the guanine nucleotide exchange factor (GEF) Son of sevenless (SOS), autoactivation is the consequence of its unique allosteric regulation. SOS activates Ras in response to receptor tyrosine kinase activation, participating in the Ras/MAPK/ERK and Ras/PI3K/AKT signaling cascades which are involved in cell proliferation, differentiation, apoptosis, and metabolism. SOS is unique from other Ras GEFs in that it is allosterically activated by its reaction product, RasGTP, in a positive feedback loop, resulting in autoactivation and temporal cooperativity. The disruption of SOS allostery is implicated in numerous diseases including cancers and RASopathies (e.g., Noonan syndrome, Costello syndrome), therefore understanding its detailed allosteric regulation is crucial. The SOS crystal structure reveals a loop that spans the allosteric site of SOS connecting its Cdc25 and REM domains, putatively named here the “allosteric loop.” Some Noonan syndrome Ras mutants may have altered interactions with this loop, but its function in SOS allostery remains unknown. This research suggests that the rigidity of the allosteric loop is important for SOS function and that it might play a role in the conformational transition from the inactive to active state of SOS. It is plausible that this surface loop could interact with other proteins or membrane lipids to modulate SOS activity, providing additional mechanisms for allostery beyond Ras binding at the allosteric site of SOS.
Keywords
SOS, Ras, Allostery, Autoactivation, Cooperativity, Temporal cooperativity
Disciplines
Biochemistry
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Johnson, Hope E., "SOS ALLOSTERIC LOOP DYNAMICS AND ITS FUNCTIONAL SIGNIFICANCE IN SOS ALLOSTERY" (2026). Chemistry & Biochemistry Dissertations. 15.
https://mavmatrix.uta.edu/chemistry_dissertations2/15