XOL-1, primary determinant of sexual fate in C. elegans, is a GHMP kinase family member and a structural prototype for a class of developmental regulators.
In Caenorhabditis elegans, an X chromosome-counting mechanism specifies sexual fate. Specific genes termed X-signal elements, which are present on the X chromosome, act in a concerted dose-dependent fashion to regulate levels of the developmental switch gene xol-1. In turn, xol-1 levels determine sexual fate and the activation state of the dosage compensation mechanism. The crystal structure of the XOL-1 protein at 1.55 A resolution unexpectedly reveals that xol-1 encodes a GHMP kinase family member, despite sequence identity of 10% or less. Because GHMP kinases, thus far, have only been characterized as small molecule kinases involved in metabolic pathways, for example, amino acid and cholesterol synthesis, XOL-1 is the first member that controls nonmetabolic processes. Biochemical investigations demonstrated that XOL-1 does not bind ATP under standard conditions, suggesting that XOL-1 acts by a mechanism distinct from that of other GHMP kinases. In addition, we have cloned a XOL-1 ortholog from Caenorhabditis briggsae, a related nematode that diverged from C. elegans approximately 50-100 million years ago. These findings demonstrate an unanticipated role for GHMP kinase family members as mediators of sexual differentiation and dosage compensation and, possibly, other aspects of differentiation and development.
Luz
John Gately
JG
Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Hassig
Christian A
CA
Pickle
Catherine
C
Godzik
Adam
A
Meyer
Barbara J
BJ
Wilson
Ian A
IA
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002107:Caenorhabditis / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins; D003001:Cloning, Molecular; D003460:Crystallization; D018360:Crystallography, X-Ray; D012734:Disorders of Sex Development / Q000235:genetics; D004303:Dosage Compensation, Genetic; D015801:Helminth Proteins / Q000737:chemistry* / Q000502:physiology*; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D019849:Sex Determination Processes; D015398:Signal Transduction; D013050:Spectrometry, Fluorescence; D014960:X Chromosome
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; C091429:XOL-1 protein, C elegans; D000255:Adenosine Triphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C021796:mevalonate kinase; C021370:homoserine kinase; D017856:Phosphotransferases (Phosphate Group Acceptor); C022371:phosphomevalonate kinase; D000251:Adenosine Triphosphatases