Kinetic proofreading models for cell signaling predict ways to escape kinetic proofreading

Area of Science:

• Cellular biology
• Biophysics
• Biochemistry

Background:

• Kinetic proofreading explains how cells distinguish ligands using dissociation rates.
• Signaling requires complete receptor modification; premature ligand dissociation halts the process.

Purpose of the Study:

• Extend kinetic proofreading models to include receptor aggregation and extrinsic kinases.
• Investigate signaling molecules (messengers) not bound to receptor complexes.
• Analyze conditions under which kinetic discrimination is lost.

Main Methods:

• Mathematical modeling of cell signaling pathways.
• Extension of the kinetic proofreading model to incorporate receptor aggregation.
• Inclusion of extrinsic kinase-dependent signaling.
• Analysis of messenger kinetics.

Main Results:

• The extended model predicts signaling modes with kinetic discrimination under certain parameters.
• For other parameter ranges, the model shows reduced or absent kinetic discrimination.
• Receptor aggregation and extrinsic kinases can lead to loss of kinetic proofreading.

Conclusions:

• The extended kinetic proofreading model provides a framework for understanding complex signaling scenarios.
• Cellular signaling can escape kinetic proofreading under specific conditions, impacting ligand discrimination.
• Model predictions are compared with experimental data for validation.