Journal of Biological Chemistry
Volume 278, Issue 49, 5 December 2003, Pages 49589-49599
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Mechanisms of Signal Transduction
Conservation of Regulatory Function in Calcium-binding Proteins: HUMAN FREQUENIN (NEURONAL CALCIUM SENSOR-1) ASSOCIATES PRODUCTIVELY WITH YEAST PHOSPHATIDYLINOSITOL 4-KINASE ISOFORM, Pik1*

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Frequenin, also known as neuronal calcium sensor-1 (NCS-1), is an N-myristoylated Ca2+-binding protein that has been conserved in both sequence and three-dimensional fold during evolution. We demonstrate using both genetic and biochemical approaches that the observed structural conservation between Saccharomyces cerevisiae frequenin (Frq1) and human NCS-1 is also reflected at the functional level. In yeast, the sole essential target of Frq1 is the phosphatidylinositol 4-kinase isoform, Pik1; both FRQ1 and PIK1 are indispensable for cell viability. Expression of human NCS-1 in yeast, but not a close relative (human KChIP2), rescues the inviability of frq1 cells. Furthermore, in vitro, Frq1 and NCS-1 (either N-myristoylated or unmyristoylated) compete for binding to a small 28-residue motif near the N terminus of Pik1. Site-directed mutagenesis indicates that the binding determinant in Pik1 is a hydrophobic α-helix and that frequenins bind to one side of this α-helix. We propose, therefore, that the function of NCS-1 in mammals may closely resemble that of Frq1 in S. cerevisiae and, hence, that frequenins in general may serve as regulators of certain isoforms of phosphatidylinositol 4-kinase.

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This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 444 (to O. P.) and by National Institutes of Health Research Grant GM21841, a grant from the Lowe Syndrome Association, and facilities provided by the Berkeley Campus Cancer Research Laboratory (to J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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These authors contributed equally to this work.