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| Title | Molecular basis of the higher-order assembly of CatSper. |
|---|---|
| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 123, Issue 2, Page e2510754123, Year 2026 |
| Publish date | Jan 13, 2026 |
 Authors | Qikui Xu / Shiyi Lin / Qingqing Zhao / Yanfei Ru / Hang Kang / Xuhui Zeng / Min Jiang / Zhen Yan / Jianping Wu /  |
| PubMed Abstract | CatSper serves as the primary Ca entry pathway in the principal piece of sperm flagellum and is crucial for sperm motility and fertility. Sperm lacking functional CatSper channels fail to undergo ...CatSper serves as the primary Ca entry pathway in the principal piece of sperm flagellum and is crucial for sperm motility and fertility. Sperm lacking functional CatSper channels fail to undergo hyperactivation during fertilization, leading to complete male infertility. Along the longitudinal axis of the sperm flagellum, staggered CatSper complexes align in a hand-in-hand arrangement, forming a distinctive quadrilinear zigzag arrays known as CatSper nanodomains. However, the molecular details of how CatSper oligomerizes to form such higher-order assembly remain unclear. In this study, we present the cryoelectron microscopy (cryo-EM) structures of native CatSper dimer (~1.5 MDa) and trimer (~2.3 MDa) megacomplexes, which represent the fundamental units of the zigzag array. We reveal the overall configuration of the zigzag assembly by characterizing the two distinct dimer interfaces that mediate CatSper oligomerization. Specifically, we elucidate the interaction details of two extracellular interfaces formed by CATSPERβ and CATSPERγ at the two dimer interfaces, respectively, and find that CATSPERη, a recently identified component of CatSper, constitutes the transmembrane interface within one of these dimer interfaces. Functional studies in mice demonstrate that CATSPERη is essential for the formation of functional CatSper on the sperm flagellum, and CATSPERη-deficient sperm fail to hyperactivate during fertilization, resulting in male infertility both in vivo and in vitro. Our data provide insights into the higher-order assembly of CatSper at the molecular level, offering clues for the development of male contraceptives. |
 External links | Proc Natl Acad Sci U S A / PubMed:41490491 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.0 - 6.8 Å |
| Structure data | EMDB-64017: The overall cryo-EM map of the mouse CatSper dimer  EMDB-64018: The local cryo-EM map of CATSPERBeta of Monomer A of the CatSper dimer  EMDB-64019: The local cryo-EM map of CATSPERGamma of Monomer A of the CatSper dimer  EMDB-64020: The local cryo-EM map of CATSPERDelta of Monomer A of the CatSper dimer  EMDB-64021: The local cryo-EM map of CATSPEREpsilon of Monomer A of the CatSper dimer  EMDB-64022: The local cryo-EM map of CATSPERBeta of Monomer B of the CatSper dimer  EMDB-64023: The local cryo-EM map of CATSPERGamma of Monomer B of the CatSper dimer  EMDB-64024: The local cryo-EM map of CATSPERDelta of Monomer B of the CatSper dimer  EMDB-64025: The local cryo-EM map of CATSPEREpsilon of Monomer B of the CatSper dimer  EMDB-64026: The local cryo-EM map of the transmembrane region of the CatSper dimer  EMDB-64027: The local cryo-EM map of the eta-eta interface of the CatSper dimer EMDB-64028: The overall cryo-EM map of the mouse CatSper trimer  EMDB-64029: The local cryo-EM map of the extracellular region of Monomer A of the CatSper trimer  EMDB-64030: The local cryo-EM map of the extracellular region of the Monomers B and A' of the CatSper trimer  EMDB-64031: The local cryo-EM map of the gamma-gamma interface of the CatSper trimer |
| Chemicals |  ChemComp-NAG:  ChemComp-CLR: |
| Source |
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 Keywords | PROTEIN TRANSPORT / sperm / hyperactivation / calcium channel |
mus musculus (house mouse)