Long-Lived Folding Intermediates Predominate the Targeting-Competent Secretome

Area of Science:

• Molecular Biology
• Biochemistry
• Cell Biology

Background:

• Secretory proteins possess signal peptides for co-translational or post-translational translocation across membranes.
• These proteins remain unfolded during transit, folding only after reaching their final destination.
• The mechanism behind this 'postponed folding' is largely attributed to signal peptides and chaperones.

Purpose of the Study:

• To investigate the mechanism of postponed folding in secretory proteins.
• To determine the role of mature domains in the targeting and folding process.
• To identify features that distinguish secretory proteins from their cytoplasmic counterparts.

Main Methods:

• Analysis of preprotein targeting and folding intermediates.
• Characterization of mature domain properties, including residue composition, disorder, and hydrophobicity.
• Comparison of folding rates between secretory and cytoplasmic protein homologs.

Main Results:

• Most mature domains maintain loosely packed, soluble folding intermediates during targeting, independent of signal peptides.
• These intermediates are crucial for recognition by translocases and are promoted by specific mature domain characteristics (composition, disorder, hydrophobicity).
• Consequently, secretory protein mature domains exhibit slower folding than cytoplasmic homologs, with some relying on signal peptides for folding, impacting solubility.

Conclusions:

• Mature domain features, rather than solely signal peptides and chaperones, are critical for postponed folding and translocase recognition.
• Secretory proteins represent a distinct class with unique folding properties impacting protein trafficking, folding, and aggregation.
• Understanding these intermediates refines models of protein biogenesis and cellular localization.