VAP-A intrinsically disordered regions enable versatile tethering at membrane contact sites

Area of Science:

• Cell Biology
• Membrane Biology
• Protein Biochemistry

Background:

• Membrane contact sites (MCSs) are crucial for cellular lipid and metabolite transfer.
• Vesicle-associated membrane protein-A (VAP-A) is a key tethereing factor at ER-involved MCSs, interacting with FFAT motif proteins.
• The mechanism by which VAP-A adapts to diverse MCSs remains unclear.

Purpose of the Study:

• To investigate the role of VAP-A intrinsically disordered regions (IDRs) in its localization and function at different MCSs.
• To elucidate how VAP-A's structural flexibility contributes to MCS organization and lipid transfer dynamics.

Main Methods:

• Human cell culture and imaging techniques.
• Genetic manipulation of VAP-A, including IDR deletion.
• Biochemical assays to assess protein interactions and lipid transfer.

Main Results:

• VAP-A localization to ER-mitochondria and ER-Golgi MCSs depends on its IDRs.
• VAP-A, via IDRs, facilitates mitochondria fusion, lipid transfer, and cardiolipin buildup at ER-mitochondria MCSs.
• IDR removal restricts VAP-A function to ER-mitochondria MCSs, suggesting IDRs confer adaptability.

Conclusions:

• Intrinsically disordered regions of VAP-A are critical for its adaptability and function across various membrane contact sites.
• VAP-A's conformational flexibility, mediated by IDRs, ensures efficient and plastic membrane tethering.
• This study provides a model for how VAP-A utilizes IDRs to navigate diverse cellular membrane contact site environments.