Protein folding in the cell: reshaping the folding funnel

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Traditional protein folding models focus on 'well-behaved' proteins refolded in vitro.
• Energy landscapes and folding funnels simplify the folding of isolated protein chains.
• Many proteins fail to fold correctly, indicating limitations in current models.

Purpose of the Study:

• To develop more comprehensive protein folding models.
• To incorporate the role of interchain interactions between partially folded intermediates.
• To describe protein folding under more physiologically relevant cellular conditions.

Main Methods:

• Extending the folding funnel concept by including additional deep minima.
• Accounting for off-pathway interchain interactions.
• Integrating the effects of cellular components like ribosomes and molecular chaperones.

Main Results:

• The enhanced folding funnel model accommodates a wider range of proteins.
• Off-pathway interactions are shown to be crucial for complex folding pathways.
• Cellular environment factors significantly influence early polypeptide chain conformations.

Conclusions:

• Current protein folding models need to incorporate interchain interactions for accuracy.
• The revised folding funnel concept provides a more realistic representation of in vivo protein folding.
• Understanding cellular influences is key to explaining diverse protein folding behaviors.