ZP2 cleavage blocks polyspermy by modulating the architecture of the egg coat
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Abstract
Following the fertilization of an egg by a single sperm, the egg coat or zona pellucida (ZP) hardens and polyspermy is irreversibly blocked. These events are associated with the cleavage of the N-terminal region (NTR) of glycoprotein ZP2, a major subunit of ZP filaments. ZP2 processing is thought to inactivate sperm binding to the ZP, but its molecular consequences and connection with ZP hardening are unknown. Biochemical and structural studies show that cleavage of ZP2 triggers its oligomerization. Moreover, the structure of a native vertebrate egg coat filament, combined with AlphaFold predictions of human ZP polymers, reveals that two protofilaments consisting of type I (ZP3) and type II (ZP1/ZP2/ZP4) components interlock into a left-handed double helix from which the NTRs of type II subunits protrude. Together, these data suggest that oligomerization of cleaved ZP2 NTRs extensively cross-links ZP filaments, rigidifying the egg coat and making it physically impenetrable to sperm.
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Cites
Highly accurate protein structure prediction with AlphaFold
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ColabFold - Making protein folding accessible to all
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“C-terminal amino acids P283-D431 of hOvst were predicted with low confidence and largely adopted the typical ribbon-like appearance of disordered protein regions 165 ; since these residues also did not contact hZP2 NTR, they were not shown in Figure 2F.”
BackgroundMethodInfluentialComparative protein structure modeling using MODELLER
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AlphaFold2: A Role for Disordered Protein/Region Prediction?
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- Authors
- Nishio, S., Emori, C., Wiseman, B., Fahrenkamp, D., Dioguardi, E., Zamora-Caballero, S., Bokhove, M., Han, L., Stsiapanava, A., Algarra, B., 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)
- Sophia University (JP)
- Center for Infectious Disease Education and Research, The University of Osaka (JP)
- Corresponding author
- Jovine, Luca
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2024-03
- Volume
- 187
- Issue
- 6
- Pages
- 1440-1459.e24
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC10976854
- OpenAlex
- W4392801959
- Cited by
- 54
- References
- 9
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 7
- FWCI
- 22.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- 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 › Public Health, Environmental and Occupational Health › 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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