Intramembranal disulfide cross-linking elucidates the super-quaternary structure of mammalian CatSpers

Reprod Biol. 2018 Mar;18(1):76-82. doi: 10.1016/j.repbio.2018.01.005. Epub 2018 Jan 20.


CatSper is a voltage-dependent calcium channel located in the plasma membrane of the sperm flagellum and is responsible for triggering hyperactive motility. A homology model for the transmembrane region was built in which the arrangement of the subunits around the pseudo-four-fold symmetry axis was deduced by the pairing of conserved transmembranal cysteines across mammals. Directly emergent of the predicted quaternary structure is an architecture in which tetramers polymerize through additional, highly conserved cysteines, creating one or more double-rows channels extending the length of the principal piece of the mammalian sperm tail. The few species that are missing these cysteines are eusocial or otherwise monogamous, suggesting that sperm competition is selective for a disulfide-crosslinked macromolecular architecture. The model suggests testable hypotheses for how CatSper channel opening might behave in response to pH, 2-arachidonoylglycerol, and mechanical force. A flippase function is hypothesized, and a source of the concomitant disulfide isomerase activity is found in CatSper-associated proteins β, δ and ε.

Keywords: Bioinformatics; Contraception; Disulfide isomerase; Disulfide linkage; Electrophysiology; Hyperactive motility; Integral membrane protein; Mechanotransduction; Sperm; sperm competition.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium Channels / chemistry
  • Calcium Channels / metabolism*
  • Computational Biology
  • Cysteine / chemistry
  • Cysteine / metabolism
  • Cystine / chemistry
  • Cystine / metabolism
  • Databases, Protein
  • Humans
  • Hydrogen-Ion Concentration
  • Ion Channels / chemistry
  • Ion Channels / metabolism*
  • Male
  • Mammals
  • Mice
  • Models, Molecular*
  • Phospholipid Transfer Proteins / chemistry
  • Phospholipid Transfer Proteins / metabolism
  • Protein Conformation
  • Protein Disulfide-Isomerases / chemistry
  • Protein Disulfide-Isomerases / metabolism
  • Protein Multimerization
  • Seminal Plasma Proteins / chemistry
  • Seminal Plasma Proteins / metabolism*
  • Sequence Alignment
  • Structural Homology, Protein


  • CATSPER3 protein, mouse
  • CATSPER4 protein, mouse
  • Calcium Channels
  • CatSper2 protein, mouse
  • Catsper1 protein, mouse
  • Ion Channels
  • Phospholipid Transfer Proteins
  • Seminal Plasma Proteins
  • Cystine
  • Protein Disulfide-Isomerases
  • Cysteine