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Genes & Dev. 17 (8): 977-990

Copyright © 2003 by Cold Spring Harbor Laboratory Press.

Vol. 17, No. 8, pp. 977-990, April 15, 2003

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

John Gately Luz,1 Christian A. Hassig,3,4,5 Catherine Pickle,3,4 Adam Godzik,6,7 Barbara J. Meyer,3,4,8 and Ian A. Wilson1,2,9

1 Department of Molecular Biology and 2 The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA; 3 Howard Hughes Medical Institute and 4 Department of Molecular and Cell Biology, University of California Berkeley, California 94720, USA

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 Å 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 ~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.

[Keywords: C. elegans; XOL-1; sexual differentiation; GHMP kinase; crystal structure]

Present addresses: 5Kalypsys, Inc., La Jolla, California 92037, USA; 6The Burnham Institute, La Jolla, California 92037, USA; 7Joint Center for Structural Genomics, San Diego Supercomputer Center, University of California San Diego, La Jolla, California 92093, USA.

8 E-MAIL bjmeyer{at}; FAX (510) 643-5584.

9 E-MAIL wilson{at}; FAX (858) 784-2980.

© 2003 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/03 $5.00

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