Established and emerging players in phospholipid scrambling: A structural perspective

Area of Science:

• Cell Biology
• Membrane Biophysics

Background:

• Cell membranes exhibit transbilayer lipid asymmetry, crucial for cellular processes.
• Phosphatidylserine (PS) is mainly in the cytosolic leaflet, while sphingolipids are in the exoplasmic leaflet at rest.
• Transbilayer lipid movement is slow, requiring scramblases for rapid responses like apoptosis.

Purpose of the Study:

• To review the diverse protein families identified with lipid scramblase activity.
• To highlight the roles of scramblases in cellular events such as apoptosis and autophagy.
• To discuss advancements in understanding scramblase mechanisms through structural and simulation studies.

Main Methods:

• Review of recent literature on lipid scramblases.
• Analysis of structural studies and in vitro reconstitution experiments.
• Molecular dynamics simulations to understand lipid transport pathways.

Main Results:

• Multiple protein families, including TMEM16, XKR, ATG9, and TMEM41B/VMP1, possess lipid scramblase activity.
• Scramblases are involved in critical cellular processes like blood clotting, apoptosis, and autophagy.
• Structural and simulation data have elucidated molecular mechanisms and transport pathways.

Conclusions:

• Lipid scramblases are essential for maintaining and rapidly altering membrane lipid asymmetry.
• Understanding scramblase function provides insights into various physiological and pathological processes.
• Some scramblases exhibit dual functions, such as TMEM16 proteins also acting as ion channels.