Structural dynamics in the evolution of a bilobed protein scaffold

Area of Science:

• Biophysics
• Evolutionary Biology
• Structural Biology

Background:

• Novel biophysical tools offer detailed insights into protein structural dynamics and their regulation.
• Understanding how structural dynamics drive protein evolution is crucial but remains poorly understood.

Purpose of the Study:

• To investigate the divergent evolution of bilobed proteins and their structural dynamics.
• To explore how modifications to a common structural core lead to functional diversification.

Main Methods:

• Structural analysis of approximately 600 bilobed proteins with a shared primordial core.
• Biophysical studies including single-molecule Förster resonance energy transfer (smFRET) and Hydrogen-Deuterium exchange mass spectrometry (HDX-MS) on selected proteins.

Main Results:

• Evolutionary modifications, particularly at the termini of the structural core, drive distinct protein dynamics.
• Diversification into transcription factors, enzymes, and transport proteins is facilitated by these altered dynamics.
• Interdomain interactions stabilize structural states, reshape active sites, and alter substrate specificity.

Conclusions:

• Evolutionary modifications of protein structural cores are a key mechanism for functional diversification.
• This study reveals a novel pathway for the emergence of functional promiscuity in proteins.
• Findings are applicable to a wide range of protein domain architectures.