Structural basis for lipid transport at membrane contact sites by the IST2-OSH6 complex

Area of Science:

• Cell Biology
• Biochemistry
• Molecular Biology

Background:

• Membrane contact sites are crucial for interorganellar lipid transport in eukaryotic cells.
• The protein IST2 tethers the endoplasmic reticulum (ER) and plasma membrane in Saccharomyces cerevisiae, playing a key role in lipid transport.
• Understanding the structural and mechanistic properties of IST2 and its interactions is vital for elucidating lipid transport pathways.

Purpose of the Study:

• To comprehensively investigate the structural and mechanistic properties of IST2.
• To elucidate the interaction between IST2 and the soluble lipid transfer protein OSH6.
• To understand the role of the IST2-OSH6 complex in lipid trafficking and explore the function of scramblases in lipid transport.

Main Methods:

• Cellular growth assays were performed.
• Biochemical studies were conducted to analyze protein interactions.
• Structural studies were employed to determine the complex's architecture.

Main Results:

• The ER-embedded transmembrane domain of IST2 functions as a constitutively active lipid scramblase, homologous to the TMEM16 family.
• The C terminus of IST2 binds to the plasma membrane and interacts with the phosphatidylserine-phosphatidylinositol 4-phosphate exchanger OSH6.
• OSH6 remains associated with IST2 during lipid shuttling, indicating a sustained interaction during transport.

Conclusions:

• The IST2-OSH6 complex plays a significant role in lipid trafficking between the ER and plasma membrane.
• This study provides initial insights into the relevance of scramblases in carrier-like lipid transport mechanisms.
• The findings contribute to a deeper understanding of lipid homeostasis and interorganellar communication in eukaryotic cells.