Protein-protein complexes can undermine ultrasensitivity-dependent biological adaptation

Area of Science:

• Biochemistry
• Systems Biology
• Molecular Signaling

Background:

• Robust perfect adaptation (RPA) is a fundamental signaling response observed across biological systems.
• Opposer modules, feedback-regulated networks with integral-computing nodes, are key architectures for RPA.
• Previous models of RPA often used simplified Michaelian kinetics, neglecting protein-protein complexes.

Purpose of the Study:

• To investigate the impact of protein-protein complexes on RPA within covalent-modification cycles.
• To develop complex-complete models that explicitly account for all molecular interactions and complexes.
• To elucidate the role of enzyme-substrate complexes in RPA dynamics.

Main Methods:

• Development of complex-complete kinetic models for interlinked covalent-modification cycles.
• Inclusion of ultrasensitivity-generating reactions within the models.
• Analysis of RPA capacity under varying conditions of protein complexation and enzyme-substrate interactions.

Main Results:

• Protein-protein complexes prevent RPA in free active protein forms.
• RPA capacity is conferred to the concentration of a larger protein pool (two distinct forms of a single protein).
• Enzyme-substrate complexes significantly reduce the input range for RPA and increase parametric requirements.

Conclusions:

• The presence of protein-protein complexes fundamentally alters the mechanism of RPA in biological networks.
• RPA is not conferred by free active protein but by a larger protein pool when complexes are present.
• Enzyme-substrate complexes play a critical, previously unrecognized role in constraining RPA, posing new questions for Opposer module design.