Crowded environments tune the fold-switching in metamorphic proteins

Area of Science:

• Biochemistry
• Structural Biology
• Molecular Biology

Background:

• Metamorphic proteins, such as KaiB and XCL1, dynamically switch structures to perform diverse biological functions.
• The intracellular environment's complexity and crowding effects on these conformational changes remain poorly understood.

Purpose of the Study:

• To investigate how crowded cellular environments affect the kinetics and thermodynamics of metamorphic proteins KaiB and XCL1.
• To elucidate the impact of crowding on protein structure, stability, and dynamics.

Main Methods:

• Utilized Nuclear Magnetic Resonance (NMR) spectroscopy to quantify protein behavior.
• Studied two well-characterized metamorphic proteins: circadian clock protein KaiB and human chemokine XCL1.
• Examined protein dynamics in physiologically relevant crowded environments.

Main Results:

• Crowded agents shifted the equilibrium towards the inactive forms of both KaiB and XCL1.
• Crowding predominantly impacted the exchange rate of XCL1 (seconds timescale) more than KaiB (hours timescale).
• Protein structures remained largely undisturbed despite altered dynamics and equilibrium.

Conclusions:

• Crowded intracellular environments influence metamorphic protein function by altering their conformational equilibrium and dynamics.
• Metamorphic proteins can rapidly adapt to environmental changes, enabling diverse cellular functions.
• This study enhances understanding of the sequence-structure-function paradigm in response to cellular environments.