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

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A conserved fertilization complex of Izumo1, Spaca6, and Tmem81 mediates sperm-egg interaction in vertebrates

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Deneke, Victoria E., Blaha, Andreas, Lu, Yonggang, Draper, Jonne M., Phan, Clara S., Panser, Karin, Schleiffer, Alexander, Jacob, Laurine, Humer, Theresa, Stejskal, Karel, Krssakova, Gabriela, Handler, Dominik, Kamoshita, Maki, Vance, Tyler D.R., Roitinger, Elisabeth, Lee, Jeffrey E., Ikawa, Masahito, Pauli, Andrea·2023·Cell
DOI 10.1101/2023.07.27.550750

Preprint — published as 10.1016/j.cell.2024.09.035 · Paper page

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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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Metadata

Authors
Deneke, V. E., Blaha, A., Lu, Y., Draper, J. M., Phan, C. S., Panser, K., Schleiffer, A., Jacob, L., Humer, T., Stejskal, K., Krssakova, G., Handler, D., Kamoshita, M., Vance, T. D. R., Roitinger, E., 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)
  • Institute of Medical Science, The University of Tokyo (JP)
Corresponding author
  • Deneke, Victoria E.
  • Pauli, Andrea
ORCID
Venue
Cell
Publisher
openRxiv
Published
2023-07-28
Volume
187
Issue
25
Pages
7066-7078.e22
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2023.07.27.550750
OpenAlex
W4403479239
Cited by
78
References
1
Citations by year
2026: 27 · 2025: 37 · 2024: 11 · 2023: 3
FWCI
29.58
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Human Frontier Science Program (LT000455/2020-L)
  • Boehringer Ingelheim
  • Government of Ontario
  • Boehringer Ingelheim Fonds
  • Ministry of Education, Culture, Sports, Science and Technology (JP19H05750, and JP21H05033, JP21H05033)
  • United States-Israel Binational Science Foundation (2020669)
  • Austrian Science Fund (1031-B28, Y 1031)
  • Israel Science Foundation (636/21)
  • Österreichische Forschungsförderungsgesellschaft
  • Boehringer Ingelheim Stiftung
  • Canadian Institutes of Health Research (153281_1, NFRFE-2019-00230)
  • European Research Council
  • Japan Society for the Promotion of Science (22K15103, 23K20043, JP19H05750, 21H05033, 24K02033)
  • Japan Science and Technology Agency (JPMJCR21N1)
  • H2020 European Research Council
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 › Reproductive Medicine › 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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