An ER translocon for multi-pass membrane protein biogenesis

Area of Science:

• Cell Biology
• Molecular Biology
• Structural Biology

Background:

• Membrane proteins with multiple transmembrane domains are vital for cellular functions.
• The biogenesis of these proteins at the endoplasmic reticulum is not well understood.

Purpose of the Study:

• To identify and characterize the machinery responsible for multi-pass membrane protein biogenesis.
• To elucidate the structural organization and function of this machinery.

Main Methods:

• Cryo-electron microscopy was used to determine the structure of the complex.
• High-throughput mRNA sequencing was employed to analyze translocon engagement.
• Cellular studies were conducted to assess the impact of accessory component depletion.

Main Results:

• A ~360 kDa ribosome-associated complex containing the Sec61 channel and five accessory factors (TMCO1, CCDC47, Nicalin-TMEM147-NOMO) was identified.
• Cryo-EM revealed a large assembly with a central membrane cavity and potential routes for transmembrane segment insertion.
• Selective translocon engagement with hundreds of multi-pass membrane proteins was observed, and depletion of accessory factors affected client protein levels (e.g., EAAT1).

Conclusions:

• A novel human translocon involved in multi-pass membrane protein biogenesis has been identified.
• The study provides a molecular framework for understanding the role of this complex in endoplasmic reticulum protein insertion.