CATSPERβ--δ Interaction Governs Hierarchical CatSper Holo-complex Assembly and is Essential for Male Fertility

The study identifies the molecular basis for the ordered assembly of the CatSper macromolecular complex, which includes the pore-forming CATSPER1-4 subunits, the canopy subcomplex (CATSPERβ–ε), a cytosolic Ca2+-sensing module (CATSPERζ–EFCAB9–ARMH2), SLCO6C1, and CATSPERθ. The authors show that the β–δ interaction is a critical nucleation step that dictates the higher-order zigzag arrangement of the complex in the flagellar membrane. Disruption of this interaction impairs complex assembly and leads to male infertility, highlighting a potential target for non-hormonal male contraceptives or diagnostic markers. The findings provide a structural framework for understanding CatSper channelopathies and flagellar function.