Protein folding in vivo revisited

Area of Science:

• Biochemistry and Molecular Biology
• Cellular Biology
• Protein Science

Background:

• Traditional models of protein folding in vivo, based on the Anfinsen postulate and molecular chaperones, have limitations in explaining complex cellular environments.
• The cellular environment significantly influences protein conformational changes, including folding, misfolding, and aggregation, making in vivo folding challenging to predict.

Purpose of the Study:

• To revisit and critically evaluate existing models of protein folding in vivo.
• To explore and discuss alternative and supplementary folding mechanisms beyond traditional molecular chaperones.
• To highlight the role of cis-acting folding helper systems and macromolecule interactions in nascent polypeptide folding.

Main Methods:

• Literature review and synthesis of existing research on protein folding mechanisms.
• Analysis of evidence supporting co-translational folding, binding partner-mediated folding, and RNA-mediated folding.
• Discussion of macromolecule-mediated folding systems, including ribosomes, membranes, and prefolded domains.

Main Results:

• Co-translational folding, binding partner-mediated folding, and RNA-mediated folding are presented as alternative or supplementary folding helpers.
• Cis-acting folding helper systems, distinct from trans-acting chaperones, are crucial for protein biogenesis and folding.
• Macromolecules' surface charges and excluded volume stabilize polypeptides against aggregation, suggesting an intrinsic chaperoning ability.

Conclusions:

• Nascent polypeptide chains can leverage the crowded cellular environment for productive folding by interacting with macromolecules.
• Macromolecules, including RNA and proteins, possess inherent chaperoning capabilities independent of their linkage to polypeptides.
• A broader understanding of protein folding requires considering diverse cellular factors beyond traditional molecular chaperones.