Cited by 78Sperm and Testicular FunctionReproductive biology and impacts on aquatic speciesReproductive Biology and Fertility

A conserved fertilization complex bridges sperm and egg in vertebrates

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Deneke, Victoria E., Blaha, Andreas, Lu, Yonggang, Suwita, Johannes P., Draper, Jonne M., Phan, Clara S., Panser, Karin, Schleiffer, Alexander +14 more·2024·Cell

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Abstract

ABSTRACT Fertilization, the fusion of sperm and egg, is essential for sexual reproduction. While several proteins have been demonstrated to be essential for the binding and fusion of gametes in vertebrates, the molecular mechanisms driving this key process are poorly understood. Here, we performed a protein interaction screen using AlphaFold-Multimer to uncover protein-protein interactions in fertilization. This screen resulted in the prediction of a trimeric complex composed of the essential fertilization factors Izumo1 and Spaca6, and Tmem81, a protein previously not implicated in fertilization. We show that Tmem81 is a conserved, testis-expressed transmembrane protein that is evolutionarily related to Izumo1 and Spaca6 and is essential for male fertility in fish and mice. Consistent with trimer formation in vivo , zebrafish izumo1 -/- , spaca6 -/- , and tmem81 -/- mutants exhibit the same sperm-egg binding defect and show co-depletion of all three proteins in sperm. Moreover, we provide experimental evidence that Izumo1, Spaca6, and Tmem81 interact in zebrafish sperm. Strikingly, the Izumo1-Spaca6 interaction is predicted to form a cleft that serves as a binding site for Bouncer, the only identified egg protein essential for fertilization in zebrafish. Together, these results provide compelling evidence for a conserved sperm factor complex in vertebrates that forms a specific interface for the sperm-egg interaction required for successful fertilization.

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Crossref · 10.1016/j.cell.2024.09.035

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Authors
Deneke, V. E., Blaha, A., Lu, Y., Suwita, J. P., Draper, J. M., Phan, C. S., Panser, K., Schleiffer, A., Jacob, L., Humer, T., Stejskal, K., Krssakova, G., Roitinger, E., Handler, D., Kamoshita, M., Vance, T. D. R., Wang, X., Surm, J. M., Moran, Y., Lee, J. E., Ikawa, M., & Pauli, A.
Affiliations
  • Research Institute of Molecular Pathology (AT)
  • University of Vienna (AT)
  • The University of Osaka Premium Research Institute for Human Metaverse Medicine (JP)
  • Institute of Molecular Biotechnology (AT)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
  • University of Toronto (CA)
  • Hebrew University of Jerusalem (IL)
  • Institute of Medical Science, The University of Tokyo (JP)
Corresponding author
  • Deneke, Victoria E.
  • Pauli, Andrea
Venue
Cell
Publisher
Elsevier BV
Published
2024-12
Volume
187
Issue
25
Pages
7066-7078.e22
ISSN
0092-8674 (ISSN-L)
OpenAlex
W4403479239
Cited by
78
References
101
Citations by year
2026: 27 · 2025: 37 · 2024: 11 · 2023: 3
FWCI
29.58
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Japan Science and Technology Agency (JPMJCR21N1)
  • Canadian Institutes of Health Research (PJT-153281)
  • Israel Science Foundation (636/21)
  • Boehringer Ingelheim Foundation
  • Government of Ontario
  • Japan Society for the Promotion of Science (JP21H05033, JP23K20043, JP24K02033, JP22K15103)
  • Human Frontier Science Program (LT000455/2020-L)
  • Ministry of Education, Culture, Sports, Science and Technology
  • Boehringer Ingelheim
  • Boehringer Ingelheim Fonds
  • FFG
  • Binational Science Foundation (2020669)
  • ERC
  • European Research Council (F80)
  • Austrian Science Fund (Y 1031-B28)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Reproductive biology and impacts on aquatic species
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
Keywords
fertilisation (biology), sperm-egg interaction, IZUMO1, bouncers, JUNO, male fertility, zebrafish, mice, protein complex formation
MeSH terms
Animals, Female, Fertilization, Humans, Immunoglobulins, Male, Membrane Proteins, Ovum, Sperm-Ovum Interactions, Spermatozoa, Zebrafish, Zebrafish Proteins, Mice

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