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Mol Cell Biol. 2015 Dec 14;36(4):645-59. doi: 10.1128/MCB.00919-15. Print 2016 Feb 15.

A Role of TMEM16E Carrying a Scrambling Domain in Sperm Motility.

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Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Laboratory of Biochemistry & Immunology, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan


Transmembrane protein 16E (TMEM16E) belongs to the TMEM16 family of proteins that have 10 transmembrane regions and appears to localize intracellularly. Although TMEM16E mutations cause bone fragility and muscular dystrophy in humans, its biochemical function is unknown. In the TMEM16 family, TMEM16A and -16B serve as Ca(2+)-dependent Cl(-) channels, while TMEM16C, -16D, -16F, -16G, and -16J support Ca(2+)-dependent phospholipid scrambling. Here, we show that TMEM16E carries a segment composed of 35 amino acids homologous to the scrambling domain in TMEM16F. When the corresponding segment of TMEM16A was replaced by this 35-amino-acid segment of TMEM16E, the chimeric molecule localized to the plasma membrane and supported Ca(2+)-dependent scrambling. We next established TMEM16E-deficient mice, which appeared to have normal skeletal muscle. However, fertility was decreased in the males. We found that TMEM16E was expressed in germ cells in early spermatogenesis and thereafter and localized to sperm tail. TMEM16E(-/-) sperm showed no apparent defect in morphology, beating, mitochondrial function, capacitation, or binding to zona pellucida. However, they showed reduced motility and inefficient fertilization of cumulus-free but zona-intact eggs in vitro. Our results suggest that TMEM16E may function as a phospholipid scramblase at inner membranes and that its defect affects sperm motility.

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