The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein

Cell. 2017 Feb 23;168(5):904-915.e10. doi: 10.1016/j.cell.2017.01.024.


Sexual reproduction is almost universal in eukaryotic life and involves the fusion of male and female haploid gametes into a diploid cell. The sperm-restricted single-pass transmembrane protein HAP2-GCS1 has been postulated to function in membrane merger. Its presence in the major eukaryotic taxa-animals, plants, and protists (including important human pathogens like Plasmodium)-suggests that many eukaryotic organisms share a common gamete fusion mechanism. Here, we report combined bioinformatic, biochemical, mutational, and X-ray crystallographic studies on the unicellular alga Chlamydomonas reinhardtii HAP2 that reveal homology to class II viral membrane fusion proteins. We further show that targeting the segment corresponding to the fusion loop by mutagenesis or by antibodies blocks gamete fusion. These results demonstrate that HAP2 is the gamete fusogen and suggest a mechanism of action akin to viral fusion, indicating a way to block Plasmodium transmission and highlighting the impact of virus-cell genetic exchanges on the evolution of eukaryotic life.

Keywords: Chlamydomonas reinhardtii; HAP2; class II fusion protein; crystal structure; gamete fusion; lipid insertion; membrane fusion; sexual reproduction; transmission-blocking malaria vaccine; virus entry.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Biological Evolution
  • Chlamydomonas / cytology
  • Chlamydomonas / metabolism*
  • Crystallography, X-Ray
  • Germ Cells / chemistry
  • Germ Cells / metabolism
  • Membrane Fusion Proteins / chemistry*
  • Membrane Fusion Proteins / genetics
  • Membrane Fusion Proteins / metabolism
  • Plant Proteins / chemistry*
  • Plant Proteins / genetics
  • Plant Proteins / metabolism
  • Plasmodium / cytology
  • Plasmodium / metabolism*
  • Protein Domains
  • Protozoan Proteins / chemistry*
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Alignment


  • Membrane Fusion Proteins
  • Plant Proteins
  • Protozoan Proteins
  • Recombinant Proteins