W0469

XOL-1, Primary Sex Determining Molecule in C. elegans, is a GHMP Kinase Family Member. John Gately Luz, Christian Hassig, Catherine Pickle, Adam Godzik, Barbara Meyer, Ian Wilson, Molecular Biology, The Scripps Research Inst., 10550 North Torrey Pines Rd., La Jolla, CA 92037 USA.

In C. elegans, sex is determined genetically by a relationship between X chromosome and autosome number. X-linked genes termed X signal elements regulate in a dose-dependent manner levels of the developmental switch gene xol-1, which in turn regulate the unfolding of sexual development and the activation state of the dosage compensation complex. The crystal structure of the XOL-1 protein unexpectedly reveals that xol-1 encodes a GHMP kinase family member, despite minimal sequence similarity. GHMP kinases have been characterized as small molecule kinases involved in metabolic pathways, e.g., amino acid and cholesterol synthesis and were not known to be involved in any developmental pathway. XOL-1 does not bind ATP under standard conditions, and, therefore, likely acts by a mechanism distinct from that of other GHMP kinases. A xol-1 ortholog cloned from the related nematode C. briggsae demonstrates that C. elegans xol-1 is not an isolated case. These results conclusively define a GHMP kinase family member as a regulator of sexual development and dosage compensation and imply that GHMP kinases may be involved in other aspects of differentiation and development.