Structure of a Ca2+-Myristoyl Switch Protein That Controls Activation of a Phosphatidylinositol 4-Kinase in Fission Yeast

• Published in: The Journal of biological chemistry Vol. 286; no. 14; pp. 12565 - 12577
• Main Authors: Lim, Sunghyuk, Strahl, Thomas, Thorner, Jeremy, Ames, James B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.04.2011; American Society for Biochemistry and Molecular Biology
• Subjects: 1-Phosphatidylinositol 4-Kinase - chemistry; 1-Phosphatidylinositol 4-Kinase - genetics; 1-Phosphatidylinositol 4-Kinase - metabolism; Amino Acid Sequence; Calcium; Calcium - metabolism; Calcium-binding Proteins; Calmodulin; Fungal Proteins - chemistry; Fungal Proteins - genetics; Fungal Proteins - metabolism; Lipid Synthesis; Magnetic Resonance Spectroscopy; Membrane Trafficking; Molecular Sequence Data; Myristic Acid - metabolism; Neurological Diseases; Neuronal Calcium-Sensor Proteins - chemistry; Neuronal Calcium-Sensor Proteins - genetics; Neuronal Calcium-Sensor Proteins - metabolism; NMR; Phosphatidylinositol Kinase; Schizosaccharomyces - enzymology; Schizosaccharomyces - genetics; Schizosaccharomyces - metabolism; Sequence Homology, Amino Acid; Signal Transduction; Membrane Trafficking; Phosphatidylinositol Kinase; NMR; Calcium; Signal Transduction; Calcium-binding Proteins; Lipid Synthesis; Neurological Diseases; Calmodulin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.208868

Neuronal calcium sensor (NCS) proteins transduce Ca2+ signals and are highly conserved from yeast to humans. We determined NMR structures of the NCS-1 homolog from fission yeast (Ncs1), which activates a phosphatidylinositol 4-kinase. Ncs1 contains an α-NH2-linked myristoyl group on a long N-terminal arm and four EF-hand motifs, three of which bind Ca2+, assembled into a compact structure. In Ca2+-free Ncs1, the N-terminal arm positions the fatty acyl chain inside a cavity near the C terminus. The C14 end of the myristate is surrounded by residues in the protein core, whereas its amide-linked (C1) end is flanked by residues at the protein surface. In Ca2+-bound Ncs1, the myristoyl group is extruded (Ca2+-myristoyl switch), exposing a prominent patch of hydrophobic residues that specifically contact phosphatidylinositol 4-kinase. The location of the buried myristate and structure of Ca2+-free Ncs1 are quite different from those in other NCS proteins. Thus, a unique remodeling of each NCS protein by its myristoyl group, and Ca2+-dependent unmasking of different residues, may explain how each family member recognizes distinct target proteins.