CATSPERT

CATSPERT (C2CD6/CatSperτ) is a membrane-associating C2 domain protein that serves as an essential targeting subunit of the sperm-specific CatSper Ca2+ channel complex required for hyperactivated motility and male fertility (PMID:34998468, PMID:34919125). It independently traffics to the sperm flagellum and, via its C2 domain-dependent interactions with ciliary trafficking machinery, directs the assembled multi-subunit CatSper complex into the quadrilinear Ca2+ signaling nanodomains of the flagellar membrane in developing spermatids (PMID:34998468). Within the complex it associates with the calcium-selective core-forming CatSper subunits and with the pH-dependent calcium sensor EFCAB9 (PMID:34919125). Loss of CatSperτ in mice depletes flagellar CatSper nanodomains, reduces CatSper currents, abolishes hyperactivation, and causes complete male sterility, yet it is dispensable for functional channel assembly per se — restoration of fertilization by Ca2+ ionophore confirms its role lies in proper localization rather than channel formation (PMID:34998468, PMID:34919125).

1. 2020 Low

   Whether C2CD6 contributes to human male infertility was unknown; identifying a candidate mutation framed it as a sperm-relevant gene before its molecular function was defined.

   Evidence Exome sequencing with Sanger confirmation in a human globozoospermia cohort

   PMID:31985809

   Open questions at the time

   • No functional validation of the missense variant performed
   • Proposed link to acrosome biogenesis not mechanistically supported and not reconciled with later flagellar channel role
2. 2022 High

   It was unknown how the CatSper complex is targeted to the flagellar membrane; CatSperτ was established as a C2 domain protein that independently traffics to the flagellum and directs the complex into its quadrilinear nanodomains, while being dispensable for channel assembly itself.

   Evidence Mouse knockout, live-cell imaging of flagellar targeting, C2 domain-function analysis, and sperm motility/fertility assays

   PMID:34998468

   Open questions at the time

   • Identity of the ciliary trafficking machinery engaged by the C2 domain not molecularly defined
   • Structural basis of nanodomain organization unresolved
3. 2022 High

   The biochemical placement of C2CD6 within the channel and the functional consequence of its loss were unresolved; it was shown to associate with core CatSper subunits and EFCAB9, with deficiency reducing CatSper currents and abolishing fertility, reversible by Ca2+ ionophore.

   Evidence Mouse knockout, Co-IP with CatSper subunits and EFCAB9, patch-clamp electrophysiology, in vitro/in vivo fertilization and rescue assays, immunofluorescence

   PMID:34919125

   Open questions at the time

   • Direct vs. indirect nature of the EFCAB9 interaction not resolved by Co-IP alone
   • Stoichiometry within the complex not determined
4. 2024 Low

   Whether C2CD6 activity is post-translationally regulated during sperm function was unaddressed; phosphoproteomics showed its phosphorylation is dysregulated by PFOS exposure alongside impaired capacitation.

   Evidence TMT-labeling Nano LC-MS/MS phosphoproteomics of PFOS-treated bull sperm

   PMID:38847481

   Open questions at the time

   • Responsible kinase/phosphatase not identified
   • Functional consequence of phosphorylation for C2CD6 activity not established

• How the C2 domain selects flagellar trafficking machinery, how CatSperτ organizes the quadrilinear nanodomain architecture, and whether human variants cause infertility through this channel-targeting role remain open.
• No structural model of CatSperτ within the CatSper complex
• Human disease causality not functionally demonstrated
• Regulatory inputs (e.g., phosphorylation) to targeting not mechanistically linked