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Peer-reviewedCC BYPLOS Biology

A histidine-mediated supramolecular mechanism links temperature and pH activation of the sperm channel CatSper

  • Billy Zhao1,2
  • Shweta Bhagwat3
  • Juan Ferreira3
  • Kiersten M Ruff4
  • Dilip K Swain1,2
  • Rohit V Pappu4
  • Celia M Santi3
  • Ziao Fu1,2
  • Polina V Lishko1,2,5
5 affiliations
  1. 1Department of Cell Biology and Physiology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
  2. 2Center for the Investigation of Membrane Excitability Diseases (CIMED), Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
  3. 3Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
  4. 4Department of Biomedical Engineering and Center for Biomolecular Condensates, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri, United States of America.
  5. 5BJC Investigator Program, Washington University School of Medicine in St. Louis, St. Louis, Missouri, United States of America.
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Abstract

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.

CatSper is a sperm-specific calcium channel essential for male fertility that is activated by changes in pH and temperature, but how these signals are integrated remains unclear. This study provides evidence suggesting that temperature-dependent histidine deprotonation within the CatSper1 N-terminus promotes neighboring complex coupling and activation.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026histidinemediated,
  title = {{A histidine-mediated supramolecular mechanism links temperature and pH activation of the sperm channel CatSper}},
  author = {Billy Zhao and Shweta Bhagwat and Juan Ferreira and Kiersten M Ruff and Dilip K Swain and Rohit V Pappu and Celia M Santi and Ziao Fu and Polina V Lishko},
  journal = {PLOS Biology},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pbio.3003776},
  url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003776},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A histidine-mediated supramolecular mechanism links temperature and pH activation of the sperm channel CatSper
AU  - Billy Zhao
AU  - Shweta Bhagwat
AU  - Juan Ferreira
AU  - Kiersten M Ruff
AU  - Dilip K Swain
AU  - Rohit V Pappu
AU  - Celia M Santi
AU  - Ziao Fu
AU  - Polina V Lishko
PY  - 2026
DA  - 2026/10/09
JO  - PLOS Biology
DO  - 10.1371/journal.pbio.3003776
UR  - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003776
AB  - 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.  CatSper is a sperm-specific calcium channel essential for male fertility that is activated by changes in pH and temperature, but how these signals are integrated remains unclear. This study provides evidence suggesting that temperature-dependent histidine deprotonation within the CatSper1 N-terminus promotes neighboring complex coupling and activation.
SN  - 1545-7885
SN  - 1544-9173
ER  -