AI Insight
This study reveals how the sperm calcium channel CatSper is activated by temperature and pH through histidine-rich regions in its structure. Researchers analyzed 47 species and found that the length and histidine content of the CatSper1 subunit correlates with species-specific fertilization temperatures, suggesting evolutionary adaptation. Using computational modeling and experiments in mouse sperm, they demonstrated that temperature-dependent changes in histidine protonation create contact interfaces between adjacent channel complexes, enabling coordinated activation of the supramolecular array.
Why it matters
Understanding CatSper's activation mechanism could inform development of male contraceptives or treatments for infertility, as this channel is essential for sperm function across animal species. The findings also provide insight into how proteins can evolve temperature sensitivity to match specific reproductive environments.
Understand the Science
by Billy Zhao, Shweta Bhagwat, Juan Ferreira, Kiersten M. Ruff, Dilip K. Swain, Rohit V. Pappu, Celia M. Santi, Ziao Fu, Polina V. Lishko
The cation channel of sperm, CatSper, is a sperm-specific calcium channel essential for male fertility across metazoans. CatSper is activated by intracellular alkalinization, membrane depolarization, and elevated temperature, which together ensure maximal current generation. However, the structural mechanisms by which these physiological stimuli jointly regulate channel activation remain poorly understood, in part because CatSper is an unusually complex ~15-subunit assembly organized in zigzag supramolecular arrays along the sperm flagellum. Here, we combine comparative genomics across 47 species with AlphaFold3-based modeling and evolutionary sequence-structure analyses to investigate a mechanism underlying temperature and pH sensitivity of CatSper. Phylogenetic analysis shows that N-terminal length and histidine enrichment of the pore-forming subunit CatSper1 strongly correlate with species-specific fertilization temperatures, suggesting evolutionary adaptation of temperature and pH sensitivity. Structural modeling further revealed conserved surface-exposed histidine clusters that form predicted contact interfaces between adjacent CatSper assemblies, with this contact interface positioned near the dominant voltage-sensing module. Functional validation using electrophysiology and calcium imaging in mouse sperm shows that capacitation-associated partial removal of the CatSper1 N-terminus selectively impairs temperature-dependent activation. Together, these findings support a model in which temperature-dependent histidine deprotonation functionally couples neighboring CatSper complexes within the supramolecular assembly, thereby promoting synchronized channel activation.