A Constitutively Active GPCR Governs Morphogenic Transitions in Cryptococcus Neoformans

EMBO J. 2009 May 6;28(9):1220-33. doi: 10.1038/emboj.2009.68. Epub 2009 Mar 26.


Sex in fungi is driven by peptide pheromones sensed through seven-transmembrane pheromone receptors. In Cryptococcus neoformans, sexual reproduction occurs through an outcrossing/heterothallic a- sexual cycle or an inbreeding/homothallic - unisexual mating process. Pheromone receptors encoded by the mating-type locus (MAT) mediate reciprocal pheromone sensing during opposite-sex mating and contribute to but are not essential for unisexual mating. A pheromone receptor-like gene, CPR2, was discovered that is not encoded by MAT and whose expression is induced during a- mating. cpr2 mutants are fertile but have a fusion defect and produce abnormal hyphal structures, whereas CPR2 overexpression elicits unisexual reproduction. When heterologously expressed in Saccharomyces cerevisiae, Cpr2 activates pheromone responses in the absence of any ligand. This constitutive activity results from an unconventional residue, Leu(222), in place of a conserved proline in transmembrane domain six; a Cpr2(L222P) mutant is no longer constitutively active. Cpr2 engages the same G-protein activated signalling cascade as the Ste3a/alpha pheromone receptors, and thereby competes for pathway activation. This study established a new paradigm in which a naturally occurring constitutively active G protein-coupled receptor governs morphogenesis in fungi.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Blotting, Northern
  • Cryptococcus neoformans / genetics
  • Cryptococcus neoformans / metabolism*
  • Cryptococcus neoformans / ultrastructure*
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism
  • Fungal Proteins / physiology*
  • Gene Expression Regulation, Fungal
  • Immunoblotting
  • Microscopy, Electron, Scanning
  • Models, Biological
  • Pheromones / metabolism
  • Protein Binding
  • Protein Multimerization
  • RGS Proteins / metabolism
  • Receptors, Pheromone / genetics
  • Receptors, Pheromone / metabolism
  • Receptors, Pheromone / physiology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae / ultrastructure
  • Signal Transduction


  • Fungal Proteins
  • Pheromones
  • RGS Proteins
  • Receptors, Pheromone