Signal sequences encode information for protein folding in the endoplasmic reticulum

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Biochemistry

Background:

• Approximately one-third of newly synthesized mammalian proteins enter the endoplasmic reticulum (ER) via the Sec61 translocon.
• The coordination between protein translocation and chaperone availability for proper protein folding in the ER is not fully understood.

Purpose of the Study:

• To investigate the role of chaperone availability in protein translocation and folding within the ER.
• To elucidate the mechanism by which signal sequences influence protein translocation and folding.

Main Methods:

• Substrate-trapping proteomics to identify accumulating nascent proteins at the Sec61 translocon.
• Analysis of protein retention and chaperone dependency based on signal sequence hydrophobicity.

Main Results:

• Marginally hydrophobic signal sequences and transmembrane domains cause retention at the Sec61 translocon, requiring the BiP chaperone for translocation.
• Sec63 is recruited to the translocation site to mediate BiP binding to nascent polypeptides, facilitating release and folding.
• Increased signal sequence hydrophobicity bypasses Sec63/BiP-dependent translocation but can lead to misfolding and aggregation if BiP is limited.

Conclusions:

• Signal sequence properties dictate the requirement for Sec63/BiP-dependent translocation, linking translocation to protein folding.
• The diversity of signal sequences and utilization of multiple translocation pathways are explained by signal sequence-guided protein folding.