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CATSPERε extracellular domains are essential for sperm calcium channel assembly and activity modulation

Jae Yeon Hwang,Huafeng Wang,Jong-Nam Oh,Jingon Kim,Sarah Finnegan,Niels E Skakkebaek,J. Chung

Published 2024 in bioRxiv

ABSTRACT

The sperm flagellar-specific CatSper Ca2+ channel is a multiprotein complex critical for successful fertilization. The four ancillary subunits, CATSPERβ, γ, δ, and ε, form a unique canopy structure over the pore-forming channel. However, how the canopy is formed and what it does in the assembled channel complex remains unknown. Here, we report that extracellular domains (ECDs) of CATSPERε are essential for canopy and holo-complex assembly and modulate channel activity during sperm capacitation. CATSPERε-deficient males are sterile due to the absence of the entire channel and defective sperm hyperactivation. Expressing ECDs-truncated CATSPERε during spermatogenesis does not rescue the knockout because it fails to incorporate into the native complex. In contrast, addition of a CATSPERε ECD fragment during sperm capacitation significantly reduces sperm hyperactivation. These findings provide insight into the underlying molecular and developmental mechanisms of CatSper assembly and how the channel can be modulated in physiological settings and by therapeutic intervention. Teaser CATSPERε extracellular domains are essential for CatSper canopy and holo-complex assembly and regulate channel activity during sperm capacitation.

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