ARMH2

ARMH2 is a cytosolic auxiliary component of the CatSper sperm calcium channel complex, where it assembles into a ternary subcomplex with EFCAB9 and CATSPERζ that supports the stable linear arrangement of CatSper nanodomains along the sperm tail and tunes the pH and Ca2+ sensitivity of the channel (PMID:41271765). Loss of ARMH2 compromises physiological CatSper activation, producing asthenozoospermia and severe subfertility (PMID:41271765). Beyond this single integrated study, no further mechanistic detail for ARMH2 has been characterized in the available corpus.

1. 2025 High

   Whether ARMH2 has any defined molecular role was unknown; this work established it as a bona fide cytosolic subunit of the CatSper channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ and is required for proper channel activation and male fertility.

   Evidence Cryo-EM, mass spectrometry, AlphaFold prediction and coevolutionary analysis defining complex membership, combined with a loss-of-function mouse model scored for sperm motility and fertility

   PMID:41271765

   Open questions at the time

   • The atomic mechanism by which ARMH2 sets pH and Ca2+ sensitivity of CatSper is not resolved
   • Direct binding interfaces within the EFCAB9–CATSPERζ–ARMH2 subcomplex are not biochemically dissected
   • Whether ARMH2 has any function outside sperm or the CatSper complex is unaddressed

• How ARMH2 is recruited and assembled into the CatSper nanodomain architecture, and the structural basis for its regulation of channel gating, remain open.
• No reconstitution defining the minimal ARMH2-containing subcomplex
• No structure of ARMH2 engaged with the gating apparatus
• Human relevance of the mouse fertility phenotype not established