Oligomerization of a molecular chaperone modulates its activity

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Molecular chaperones are crucial for protein folding but their mechanisms remain unclear.
• Trigger Factor (TF) is an ATP-independent chaperone influencing protein folding.
• Understanding TF's structure-function relationship is key to elucidating chaperone mechanisms.

Purpose of the Study:

• To investigate the contrasting effects of monomeric and dimeric Trigger Factor (TF) on non-native protein folding.
• To determine the atomic resolution structure of dimeric TF and correlate it with its chaperone activity.
• To understand how TF's quaternary structure modulates its function.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was employed to determine the structure of dimeric TF.
• Comparative analysis of monomeric and dimeric TF's affinity, association rates, and holdase activity.
• Structural insights were correlated with functional observations.

Main Results:

• The 100 kDa dimeric TF structure revealed buried substrate-binding sites at the dimeric interface, explaining lower affinity compared to monomeric TF.
• Despite lower affinity, dimeric TF showed faster protein association, enhanced anti-aggregation, and stronger holdase activity.
• Dimeric TF forms a cavity where substrate-binding sites create a contiguous surface, facilitating accelerated association with unfolded proteins.

Conclusions:

• The quaternary structure of Trigger Factor (TF) significantly modulates its chaperone activity.
• Dimeric TF's unique structural arrangement enhances its ability to bind unfolded proteins rapidly and prevent aggregation.
• This study demonstrates how chaperone function can be regulated by conformational changes, leading to distinct cellular outcomes.