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Cryo-EM structure of the cytosolic ARMH2-EFCAB9-CATSPERz subcomplex of the mouse CatSpermasome
Structural highlights
FunctionEFCB9_MOUSE Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation (PubMed:31056283, PubMed:34225353). pH-dependent Ca(2+) sensor required to activate the CatSper channel (PubMed:31056283). Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization (PubMed:31056283). Associates with the CatSper complex via direct interaction with CATSPERZ, and senses intracellular Ca(2+) (PubMed:31056283). Together with CATSPERZ, associates with the CatSper channel pore and is required for the two-row structure of each single CatSper channel (PubMed:31056283).[1] [2] Publication Abstract from PubMedSperm capacitation and fertilization are highly regulated by Ca(2+) signaling. CatSper, a sperm-specific calcium channel, plays a crucial role in sperm hyperactivated motility and fertility by mediating Ca(2+) influx into sperm. CatSper is the most complicated ion channel known, comprising the pore-forming CATSPER1-4 and multiple auxiliary subunits. However, our previous structural study of mouse CatSper suggests the presence of potential component(s) that remain to be identified. The identity and functional significance of the missing piece(s) of CatSper remain elusive. Here, by combining cryo-EM, mass spectrometry, AlphaFold structure prediction, and coevolutionary analysis, we identify armadillo-like helical domain containing 2 (ARMH2) as a cytosolic component of CatSper. ARMH2 forms a cytosolic ternary subcomplex with EFCAB9 and CATSPERzeta, which contributes to the stable assembly of the linear arrangement of CatSper nanodomains along the sperm tail and regulates the pH and Ca(2+) sensitivity of the channel. Loss of ARMH2 leads to compromised physiological activation of CatSper, thereby resulting in asthenozoospermia and severe subfertility. These findings show that ARMH2 is crucial for sperm function and provide fresh insights into the composition and functional regulation of CatSper. The integrated methodology employed in identifying ARMH2 also provides valuable approaches for discovering uncharacterized components in other protein complexes. ARMH2 is a cytosolic component of CatSper crucial for sperm function.,Zhao Q, Lin S, Kang H, Ru Y, Xu Q, Yu Z, Huang X, De Rito C, Sassi G, Wang S, Sun S, Sun R, Cheng H, Zhu Y, Liu M, Zhang Y, Jiang M, Percudani R, Chung JJ, Zeng X, Yan Z, Wu J Nat Commun. 2025 Nov 21;16(1):10243. doi: 10.1038/s41467-025-65952-0. PMID:41271765[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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