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PreprintCited by 54Reproductive Biology and FertilitySperm and Testicular FunctionReproductive biology and impacts on aquatic species

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Architecture of the vertebrate egg coat and structural basis of the ZP2 block to polyspermy

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Nishio, Shunsuke, Emori, Chihiro, Wiseman, Benjamin, Fahrenkamp, Dirk, Dioguardi, Elisa, Zamora-Caballero, Sara, Bokhove, Marcel, Han, Ling, Stsiapanava, Alena, Lu, Yonggang, Kodani, Mayo, Bainbridge, Rachel E., Komondor, Kayla M., Carlson, Anne E., Landreh, Michael, de Sanctis, Daniele, Yasumasu, Shigeki, Ikawa, Masahito, Jovine, Luca·2023·Cell
DOI 10.1101/2023.06.21.544075PMC PMC10976854

Preprint — published as 10.1016/j.cell.2024.02.013 · Paper page

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Abstract

SUMMARY: Post-fertilization cleavage of glycoprotein ZP2, a major subunit of egg zona pellucida (ZP) filaments, is crucial for mammalian reproduction by irreversibly blocking polyspermy. ZP2 processing is thought to inactivate a sperm-binding activity located upstream of the protein’s cleavage site; however, its molecular consequences and connection with ZP hardening are unknown. Here we report X-ray crystallographic, cryo-EM and biochemical studies showing that cleavage of ZP2 triggers its oligomerization. Deletion of the ZP-N1 domain that precedes the cleavage site of mouse ZP2 allows it to homodimerize even without processing, and animals homozygous for this variant are subfertile by having a semi-hardened ZP that allows sperm attachment but hinders penetration. Combined with the structure of a native egg coat filament, which reveals the molecular basis of heteromeric ZP subunit interaction, this suggests that oligomerization of cleaved ZP2 cross-links the ZP, rigidifying it and making it physically impenetrable to sperm.

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Metadata

Authors
Nishio, S., Emori, C., Wiseman, B., Fahrenkamp, D., Dioguardi, E., Zamora-Caballero, S., Bokhove, M., Han, L., Stsiapanava, A., Lu, Y., Kodani, M., Bainbridge, R. E., Komondor, K. M., Carlson, A. E., Landreh, M., de Sanctis, D., Yasumasu, S., Ikawa, M., & Jovine, L.
Affiliations
  • Karolinska Institutet (SE)
  • Immunology Frontier Research Center, The University of Osaka (JP)
  • Research Institute for Microbial Diseases, The University of Osaka (JP)
  • University of Pittsburgh (US)
  • Uppsala University (SE)
  • European Synchrotron Radiation Facility (FR)
  • Sophia University (JP)
  • Center for Infectious Disease Education and Research, The University of Osaka (JP)
Corresponding author
Jovine, Luca
ORCID
Venue
Cell
Publisher
openRxiv
Published
2023-06-22
Volume
187
Issue
6
Pages
1440-1459.e24
ISSN
0092-8674 (ISSN-L)
DOI
10.1101/2023.06.21.544075
PMC
PMC10976854
OpenAlex
W4392801959
Cited by
54
References
1
Citations by year
2026: 21 · 2025: 26 · 2024: 7
FWCI
22.37
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)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • HZB Repository (Helmholtz-Zentrum Berlin für Materialien und Energie GmbH (HZB)) (submittedVersion, other-oa)
Funders
  • Diamond Light Source
  • Kempe Foundation
  • DeepMind
  • Deutsche Forschungsgemeinschaft (401763100)
  • European Synchrotron Radiation Facility
  • Knut och Alice Wallenbergs Stiftelse (2018.0042)
  • Vetenskapsrådet (2016-03999, 2020-04936, 2019-01961)
  • Kempestiftelserna
  • Fukushima University
  • Stockholms Universitet
  • Science for Life Laboratory
  • National Institutes of Health
  • Helmholtz-Zentrum Berlin für Materialien und Energie
  • Japan Society for the Promotion of Science (23K05879, 22K15103, 20K06774, 19H05750, 23K20043, 21H05033, 24K02033)
  • Center for Innovative Medicine
  • National Institute of General Medical Sciences (R01GM125638)
Topics
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
  • Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Reproductive biology and impacts on aquatic species
Keywords
zona pellucida, ZP2, polyspermy block, N-terminal cleavage, protein oligomerization, ZP3, ZP1, ZP4, sperm binding, fertilisation (biology), DNA double helix
MeSH terms
Zona Pellucida Glycoproteins, Female, Glycoproteins, Humans, Male, Ovum, Semen, Spermatozoa, Zona Pellucida

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