Crystal structure of the ZP-N domain of ZP3 reveals the core fold of animal egg coats

Nature. 2008 Dec 4;456(7222):653-7. doi: 10.1038/nature07599.


Species-specific recognition between the egg extracellular matrix (zona pellucida) and sperm is the first, crucial step of mammalian fertilization. Zona pellucida filament components ZP3 and ZP2 act as sperm receptors, and mice lacking either of the corresponding genes produce oocytes without a zona pellucida and are completely infertile. Like their counterparts in the vitelline envelope of non-mammalian eggs and many other secreted eukaryotic proteins, zona pellucida subunits polymerize using a 'zona pellucida (ZP) domain' module, whose conserved amino-terminal part (ZP-N) was suggested to constitute a domain of its own. No atomic structure has been reported for ZP domain proteins, and there is no structural information on any conserved vertebrate protein that is essential for fertilization and directly involved in egg-sperm binding. Here we describe the 2.3 ångström (A) resolution structure of the ZP-N fragment of mouse primary sperm receptor ZP3. The ZP-N fold defines a new immunoglobulin superfamily subtype with a beta-sheet extension characterized by an E' strand and an invariant tyrosine residue implicated in polymerization. The structure strongly supports the presence of ZP-N repeats within the N-terminal region of ZP2 and other vertebrate zona pellucida/vitelline envelope proteins, with implications for overall egg coat architecture, the post-fertilization block to polyspermy and speciation. Moreover, it provides an important framework for understanding human diseases caused by mutations in ZP domain proteins and developing new methods of non-hormonal contraception.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • CHO Cells
  • Conserved Sequence
  • Cricetinae
  • Cricetulus
  • Crystallization
  • Crystallography, X-Ray
  • Egg Proteins / chemistry*
  • Egg Proteins / genetics
  • Egg Proteins / metabolism*
  • Female
  • Male
  • Membrane Glycoproteins / chemistry*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Ovum / chemistry*
  • Ovum / metabolism*
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Folding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Repetitive Sequences, Amino Acid
  • Spermatozoa / metabolism
  • Zona Pellucida Glycoproteins


  • Egg Proteins
  • Membrane Glycoproteins
  • Peptide Fragments
  • Receptors, Cell Surface
  • ZP2 protein, human
  • ZP3 protein, human
  • Zona Pellucida Glycoproteins
  • Zp2 protein, mouse
  • Zp3 protein, mouse

Associated data

  • PDB/3D4C
  • PDB/3D4G
  • PDB/3EF7