Crystal structures of the kinase domain of Schizosaccharomyces pombe Asp1
2Molecular Biology Program, Memorial Sloan Kettering Cancer Center, USA
Inositol pyrophosphates (IPPs) are signaling molecules that regulate cellular phosphate homeostasis in diverse eukaryal taxa. In fission yeast, mutations that increase 1,5-IP8 derepress the PHO regulon while mutations that ablate IP8 synthesis are PHO hyperrepressive. Fission yeast Asp1, the principal agent of 1,5-IP8 dynamics, is a bifunctional enzyme composed of an N-terminal IPP kinase domain and a C-terminal IPP pyrophosphatase domain. We report here six crystal structures of the kinase domain of Schizosaccharomyces pombe Asp1 in the presence of substrates, products, and metal cofactors. The structures revealed that the enzyme adopts an “ATP- grasp” fold. A second protomer in the asymmetric unit lacked substrates in its active site and adopted an open conformation as compared to the enzyme with bound substrates. We present a model of enzyme ligand recognition in which active site opening and closing facilitates substrate binding, catalysis, and product release. These findings increase our understanding of an enzyme involved in phosphate homeostasis and transcription termination.