Structural Biology

Kinaselike Structures in Sexual Specification Proteins

Science's STKE  29 Apr 2003:
Vol. 2003, Issue 180, pp. tw171-TW171
DOI: 10.1126/stke.2003.180.tw171

The specification of sex involves either the presence or absence of a particular chromosome (the Y chromosome in mammals) along with dosage compensation, or the number of X chromosomes (for example, in the model organisms nematode and fruit fly). In C. elegans XOL-1 protein governs gender--high levels of XOL-1 produce males and low levels produce hermaphrodites. The presence of two X chromosomes in the hermaphrodites results in the expression of xol-1 repressors. Beyond the genetic evidence linking xol-1 to sexual differentiation, little is know regarding the function of the XOL-1 protein. Luz et al. crystallized XOL-1 to gain insight into its function. Surprisingly, despite no primary sequence similarity to GHMP kinases, the protein folded into a structure very similar to that of GHMP kinases, which catalyze small molecular metabolism. Indeed, the family is named for the first members identified, galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase. Despite the overall structural similarity, differences in specific residues predict that XOL-1 will not bind adenosine triphosphate (ATP), and in vitro, no ATP binding or hydrolysis by XOL-1 was detected. The structural differences suggested that XOL-1 may be regulated by a small molecule ligand. In yeast, GHMP-like kinases have been identified that act as transcriptional regulators or even as bifunctional proteins with transcription regulatory activity and kinase activity. Thus, the GHMP-like structure appears to be a dual-function motif, with roles outside of metabolism, involved in development and sexual specification.

J. G. Luz, C.A. Hassig, C. Pickle, A. Godzik, B. J. Meyer, I. A. Wilson, 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. Genes Dev. 17, 977-990 (2003). [Abstract] [Full Text]