ARMH2 is a cytosolic component of CatSper crucial for sperm function

Qingqing Zhao, Shiyi Lin, Hang Kang, Yanfei Ru, Qikui Xu, Zijing Yu, Xiaofang Huang, Carlo De Rito, Giulia Sassi, Shaojie Wang, Shuya Sun, Rui Sun, Honghan Cheng, Yi Zhu, Mingxi Liu, Yongdeng Zhang, Min Jiang, Riccardo Percudani, Jean-Ju Chung, Xuhui Zeng (), Zhen Yan () and Jianping Wu ()
Additional contact information
Qingqing Zhao: Fudan University
Shiyi Lin: Fudan University
Hang Kang: Nantong University, Institute of Reproductive Medicine, Medical school
Yanfei Ru: Westlake Laboratory of Life Sciences and Biomedicine
Qikui Xu: Westlake University, Key Laboratory of Structural Biology of Zhejiang Province, State Key Laboratory of Gene Expression, School of Life Sciences
Zijing Yu: Westlake Laboratory of Life Sciences and Biomedicine
Xiaofang Huang: Yale University, Department of Cellular and Molecular Physiology, Yale School of Medicine
Carlo De Rito: University of Parma, Department of Chemistry, Life Sciences, and Environmental Sustainability
Giulia Sassi: University of Parma, Department of Chemistry, Life Sciences, and Environmental Sustainability
Shaojie Wang: Westlake University, Key Laboratory of Structural Biology of Zhejiang Province, State Key Laboratory of Gene Expression, School of Life Sciences
Shuya Sun: Nanjing Medical University, State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences
Rui Sun: Westlake University, School of Medicine
Honghan Cheng: Westlake University, School of Medicine
Yi Zhu: Westlake University, School of Medicine
Mingxi Liu: Nanjing Medical University, State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Histology and Embryology, School of Basic Medical Sciences
Yongdeng Zhang: Westlake Laboratory of Life Sciences and Biomedicine
Min Jiang: Westlake Laboratory of Life Sciences and Biomedicine
Riccardo Percudani: University of Parma, Department of Chemistry, Life Sciences, and Environmental Sustainability
Jean-Ju Chung: Yale University, Department of Cellular and Molecular Physiology, Yale School of Medicine
Xuhui Zeng: Nantong University, Institute of Reproductive Medicine, Medical school
Zhen Yan: Westlake University, Key Laboratory of Structural Biology of Zhejiang Province, State Key Laboratory of Gene Expression, School of Life Sciences
Jianping Wu: Westlake University, Key Laboratory of Structural Biology of Zhejiang Province, State Key Laboratory of Gene Expression, School of Life Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract Sperm capacitation and fertilization are highly regulated by Ca2+ signaling. CatSper, a sperm-specific calcium channel, plays a crucial role in sperm hyperactivated motility and fertility by mediating Ca2+ 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 CATSPERζ, which contributes to the stable assembly of the linear arrangement of CatSper nanodomains along the sperm tail and regulates the pH and Ca2+ 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.

Date: 2025
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DOI: 10.1038/s41467-025-65952-0

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