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Updated: May 19, 2026
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Published on: November 27, 2013
Evolution of Protein Regulation in the Vertebrate Glucose Sensor
Biorxiv : the Preprint Server for Biology
|May 18, 2026
Summary
Evolutionary resurrection of ancient proteins revealed how glucokinase (GCK) gained allosteric regulation and formed inhibitory interactions with glucokinase regulatory protein (GKRP). This demonstrates how new protein regulatory strategies emerge through conformational changes.
Area of Science:
- Biochemistry
- Evolutionary Biology
- Structural Biology
Background:
- Protein regulation is crucial for cellular function, yet the evolutionary origins of new regulatory mechanisms remain poorly understood.
- Glucokinase (GCK), a key regulator of glucose homeostasis, exhibits complex control through allostery and interactions with glucokinase regulatory protein (GKRP).
Purpose of the Study:
- To investigate the evolutionary history and molecular basis of protein regulation in glucokinase (GCK) and glucokinase regulatory protein (GKRP).
- To understand how novel regulatory strategies emerge and evolve in key homeostatic proteins.
Main Methods:
- Resurrecting extinct GCK and GKRP proteins using a vertical evolutionary approach.
- Employing enzyme kinetics, limited proteolysis, hydrogen-deuterium exchange, high-resolution NMR, and X-ray crystallography.
- Analyzing conformational dynamics and protein-protein interactions.
Main Results:
- An ancestral GCK precursor evolved monomeric allostery via conformational expansion, including an intrinsically disordered substrate binding loop without sequence changes.
- A hydrophobic cleft emerged in GCK due to this conformational expansion.
- The GCK-GKRP interaction arose from a GKRP loop insertion exapting GCK's hydrophobic patch, creating an inhibitory complex.
Conclusions:
- Multiple distinct regulatory strategies can emerge through evolutionary addition of novel protein conformations.
- This study provides a general mechanism for the evolution of heteromeric protein-protein interactions and allosteric regulation.
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