Protein folding. Translational tuning optimizes nascent protein folding in cells

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Cellular protein synthesis and folding are complex processes.
• Understanding cotranslational folding mechanisms is challenging.
• The cystic fibrosis transmembrane conductance regulator (CFTR) is crucial for cellular function.

Purpose of the Study:

• To investigate the cotranslational folding mechanisms of the CFTR N-terminal domain.
• To elucidate the role of subdomain folding timing in protein biogenesis.
• To identify cellular strategies that optimize cotranslational folding.

Main Methods:

• Fluorescence resonance energy transfer (FRET) was employed to monitor folding.
• The study focused on the first nucleotide-binding domain of CFTR.
• Experimental conditions were manipulated to assess folding modulation.

Main Results:

• Cotranslational folding occurred through sequential compaction of distinct subdomains.
• The timing of α-subdomain folding was critical, impacting subsequent core formation.
• Modulating folding propensity via delayed compaction, β-strand intercalation, and codon optimization enhanced folding.

Conclusions:

• De novo protein folding is dynamically regulated during translation.
• Cellular mechanisms integrate synthesis and folding for efficiency.
• Translation kinetics and subdomain folding timing are key determinants of the folding landscape.