An intramembrane chaperone complex facilitates membrane protein biogenesis.

Area of Science:

• Cell Biology
• Molecular Biology
• Protein Biochemistry

Background:

• Integral membrane proteins constitute ~25% of genes and are processed in the endoplasmic reticulum (ER).
• Mechanisms for targeting and inserting single transmembrane domains (TMDs) are known, but multi-spanning membrane protein assembly is poorly understood.
• Hydrophilic amino acids in TMDs require chaperoning during biogenesis, yet ER-resident intramembrane chaperones are largely undefined.

Purpose of the Study:

• To identify and characterize ER-resident intramembrane chaperones involved in multi-spanning membrane protein assembly.
• To elucidate the role of novel chaperones in protecting and folding transmembrane domains within the lipid bilayer.

Main Methods:

• Identification of the PAT complex, a heterodimer of CCDC47 and Asterix.
• Analysis of PAT complex engagement with nascent transmembrane domains (TMDs).
• Assessment of multi-spanning membrane protein biogenesis in cells lacking PAT complex subunits.

Main Results:

• The PAT complex, composed of CCDC47 and Asterix, is identified as an abundant ER-resident intramembrane chaperone.
• The PAT complex binds to nascent TMDs with unshielded hydrophilic side chains within the lipid bilayer.
• Loss of either PAT complex subunit impairs the biogenesis of multiple multi-spanning membrane proteins.

Conclusions:

• The PAT complex functions as an essential intramembrane chaperone during the assembly of multi-spanning membrane proteins.
• This chaperone activity protects TMDs, minimizes misfolding, and is crucial for cellular protein homeostasis.
• The discovery of the PAT complex provides new insights into the fundamental processes of membrane protein biogenesis.