한빛사논문
Jae Yeon Hwang,1 Nadja Mannowetz,4 Yongdeng Zhang,2 Robert A. Everley,5 Steven P. Gygi,5 Joerg Bewersdorf,2 Polina V. Lishko,4 and Jean-Ju Chung1,3,6,*
1 Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA
2 Department of Cell Biology, Yale School of Medicine, New Haven, CT 06510, USA
3 Department of Gynecology and Obstetrics, Yale School of Medicine, New Haven, CT 06510, USA
4 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
5 Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
6 Lead Contact
*Corresponding author
Abstract
Varying pH of luminal fluid along the female reproductive tract is a physiological cue that modulates sperm motility. CatSper is a sperm-specific, pH-sensitive calcium channel essential for hyperactivated motility and male fertility. Multi-subunit CatSper channel complexes organize linear Ca2+ signaling nanodomains along the sperm tail. Here, we identify EF-hand calcium-binding domain-containing protein 9 (EFCAB9) as a bifunctional, cytoplasmic machine modulating the channel activity and the domain organization of CatSper. Knockout mice studies demonstrate that EFCAB9, in complex with the CatSper subunit, CATSPERζ, is essential for pH-dependent and Ca2+-sensitive activation of the CatSper channel. In the absence of EFCAB9, sperm motility and fertility is compromised, and the linear arrangement of the Ca2+ signaling domains is disrupted. EFCAB9 interacts directly with CATSPERζ in a Ca2+ -dependent manner and dissociates at elevated pH. These observations suggest that EFCAB9 is a long-sought, intracellular, pH-dependent Ca2+ sensor that triggers changes in sperm motility.
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