Abstract
CatSper is a highly specialized Ca2+ channel mediating Ca2+ entry in spermatozoa, which is essential for sperm motility and fertility. CatSper dysfunction would lead to male infertility, and it has been an attractive target for male infertility treatment as well as development of novel non-hormonal contraceptives. CatSper is the most complex ion channel known, consisting of at least ten identified subunits. It is very different from classic Cav channels in many aspects. For instance, the ion conducting pore of CatSper consists of four separate chains CatSper1-4 instead of a single chain in Cav channels. The auxiliary subunits CatSperβ, γ, δ, ε contain large extracellular domains while none of them are homologous to the α2δ subunit of Cav channels, indicating unique assembly of CatSper. To provide structural insights into CatSper composition, assembly, and regulation mechanisms, we purified the native CatSper channel from mouse testicular and epididymal tissues and resolved its structure at an overall resolution of 2.9 Å by cryo-EM. In the extracellular view, CatSper1-4 heterotetramer conform to the conventional domain-swapped voltage-gated ion channel fold, following a counterclockwise arrangement. CatSperβ, γ, δ and ε—each of which contains a single transmembrane segment and a large extracellular domain—constitute a pavilion-like structure that stabilizes the entire complex through interactions with CatSper4, 1, 3 and 2, respectively. Besides, the high-resolution EM map reveals several previously uncharacterized components, including TMEM249, TMEM262 (also named CatSperη) and an organic anion transporter SLCO6C1. Thus, CatSper is actually a channel-transporter ultracomplex that we termed the CatSpermasome. The structure and assembly details of the CatSpermasome revealed by our study help to lay the foundation for the development of CatSpermasome-related treatments for male infertility and non-hormonal contraceptives.
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