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bioRxiv · 10.1101/2021.07.06.451342

C2CD6 is required for assembly of the CatSper calcium channel complex and fertilization

Yang, F.·Gervasi, M. G.·Leu, N. A.·Tourzani, D. A.·Ruthel, G.·Visconti, P. E.·Wang, J.
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Abstract

The CatSper cation channel is essential for sperm capacitation and male fertility. The multi-subunit CatSper complexes form highly organized calcium signaling nanodomains on flagellar membranes. Here we report identification of an uncharacterized protein C2CD6 as a novel subunit of the CatSper ion channel complex. C2CD6 contains a calcium-dependent membrane targeting C2 domain. C2CD6 interacts with the CatSper calcium-selective core forming subunits. Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male sterility. C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both in vitro and in vivo. Interestingly, transient treatments with either Ca2+ ionophore, starvation, or a combination of both restore the fertilization capacity of C2CD6-deficient sperm in vitro. C2CD6 interacts with EFCAB9, a pH-dependent calcium sensor in the CatSper complex. We postulate that C2CD6 may regulate CatSper assembly, target the CatSper complex to flagellar plasma membrane, and function as a calcium sensor. The identification of C2CD6 as an essential subunit may facilitate the long-sought reconstitution of the CatSper ion channel complex in a heterologous system for male contraceptive development.

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Yang, F., Gervasi, M. G., Leu, N. A., Tourzani, D. A., Ruthel, G., Visconti, P. E., Wang, J.. 2021-07-06. C2CD6 is required for assembly of the CatSper calcium channel complex and fertilization. https://doi.org/10.1101/2021.07.06.451342

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