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Updated: Sep 23, 2025
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A Fluorescence-based Assay of Phospholipid Scramblase Activity
Published on: September 20, 2016
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TMEM16 scramblases thin the membrane to enable lipid scrambling
Maria E Falzone1,2, Zhang Feng1, Omar E Alvarenga1,3
1Department of Anesthesiology, Weill Cornell Medical College, New York, NY, USA.
Nature Communications
|May 13, 2022
Summary
This study reveals that TMEM16 scramblases thin cell membranes to facilitate lipid movement, challenging the necessity of an open hydrophilic groove for this process. This finding offers a new perspective on scramblase mechanisms.
Area of Science:
- Membrane biology
- Protein structure and function
- Lipid dynamics
Background:
- TMEM16 scramblases are crucial for regulating plasma membrane lipid asymmetry in eukaryotes.
- Previous models proposed lipid headgroups move through a membrane-spanning hydrophilic groove.
- Direct evidence of lipid-protein interactions within the scramblase groove was lacking.
Purpose of the Study:
- To elucidate the structural basis of TMEM16 scramblase activity.
- To investigate the role of the hydrophilic groove in lipid scrambling.
- To determine the mechanism by which TMEM16 facilitates transbilayer lipid movement.
Main Methods:
- Cryo-electron microscopy (cryo-EM) at 2.3 Å resolution.
- Reconstitution of the calcium-bound afTMEM16 scramblase in nanodiscs.
- Site-directed mutagenesis to probe protein-lipid interactions.
Main Results:
- The structure reveals membrane thinning induced by lipid rearrangement at the pathway.
- Lipid interactions are primarily observed in the intracellular vestibule of the groove.
- Scrambling occurs in thinner membranes and is independent of a consistently open groove.
Conclusions:
- afTMEM16 thins the membrane to enable lipid scrambling, rather than solely relying on a hydrophilic groove.
- An open pathway is not a strict requirement for rapid transbilayer lipid movement.
- This mechanism may apply to other types of scramblases, including those without a distinct hydrophilic groove.
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