Calcium-dependent phospholipid scrambling by TMEM16F
Jun Suzuki1, Masato Umeda, Peter J Sims
1Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
Nature
|November 26, 2010
Summary
Transmembrane protein 16F (TMEM16F) is crucial for calcium-dependent phosphatidylserine (PtdSer) exposure on cell surfaces. Mutations in TMEM16F cause Scott syndrome, a disorder linked to defective phospholipid scrambling.
Area of Science:
- Cell Biology
- Biochemistry
- Membrane Biophysics
Background:
- Phospholipids are asymmetrically distributed in animal cell plasma membranes.
- Disrupted phospholipid asymmetry, like phosphatidylserine (PtdSer) exposure on activated platelets, triggers biological processes such as blood clotting.
- The molecular mechanism of Ca(2+)-dependent phospholipid scrambling, mediated by scramblases, remains largely unknown.
Purpose of the Study:
- To identify the molecular component responsible for Ca(2+)-dependent phosphatidylserine (PtdSer) exposure.
- To elucidate the mechanism underlying phospholipid scrambling in cellular systems.
Main Methods:
- Expression cloning using a mouse B-cell line (Ba/F3) engineered for enhanced PtdSer exposure.
- Site-directed mutagenesis and functional assays of TMEM16F.
- Analysis of a patient with Scott syndrome carrying a TMEM16F gene mutation.
Main Results:
- TMEM16F was identified as an essential component for Ca(2+)-dependent PtdSer exposure.
- A constitutively active mutant of TMEM16F induced spontaneous PtdSer exposure.
- Wild-type TMEM16F localized to the plasma membrane and mediated Ca(2+)-dependent phospholipid scrambling.
- A Scott syndrome patient exhibited a TMEM16F mutation leading to premature protein termination.
Conclusions:
- TMEM16F is a key player in regulating phospholipid asymmetry and PtdSer exposure.
- TMEM16F functions as a Ca(2+)-dependent phospholipid scramblase.
- Defects in TMEM16F are directly implicated in Scott syndrome, highlighting its clinical relevance.
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