Structural Studies of Inositol 1,4,5-Trisphosphate Receptor: COUPLING LIGAND BINDING TO CHANNEL GATING

• Published in: The Journal of biological chemistry Vol. 285; no. 46; pp. 36092 - 36099
• Main Authors: Chan, Jenny, Yamazaki, Haruka, Ishiyama, Noboru, Seo, Min-Duk, Mal, Tapas K, Michikawa, Takayuki, Mikoshiba, Katsuhiko, Ikura, Mitsuhiko
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 12-11-2010
• Subjects: Amino Acid Sequence; AMINO ACIDS; Animals; AROMATICS; Binding Sites - genetics; CALCIUM; CRYSTAL STRUCTURE; Crystallography, X-Ray; INOSITOL; Inositol 1,4,5-Trisphosphate - chemistry; Inositol 1,4,5-Trisphosphate - metabolism; Inositol 1,4,5-Trisphosphate Receptors - chemistry; Inositol 1,4,5-Trisphosphate Receptors - genetics; Inositol 1,4,5-Trisphosphate Receptors - metabolism; Ion Channel Gating - genetics; Ion Channel Gating - physiology; Ligands; Magnetic Resonance Spectroscopy; MATERIALS SCIENCE; Mice; Models, Molecular; Molecular Sequence Data; Mutation; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Protein Structure and Folding; Protein Structure, Secondary; Protein Structure, Tertiary; RESIDUES; Sequence Homology, Amino Acid; Tryptophan - chemistry; Tryptophan - genetics; Tryptophan - metabolism; Tyrosine - chemistry; Tyrosine - genetics; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.140160

The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP₃R) exhibit distinct IP₃ sensitivities and cooperativities in calcium (Ca²⁺) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP₃R. We determined the 1.9 Å crystal structure of the suppressor domain from type 3 IP₃R (IP₃R3SUP, amino acids 1-224) and revealed structural features contributing to isoform-specific functionality of IP₃R by comparing it with our previously determined structure of the type 1 suppressor domain (IP₃R1SUP). The molecular surface known to associate with the ligand binding domain (amino acids 224-604) showed marked differences between IP₃R3SUP and IP₃R1SUP. Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP₃R1 and Glu-19, Trp-168, and Ser-218 in IP₃R3) within the N-terminal suppressor domains of IP₃R1SUP and IP₃R3SUP interact directly with their respective C-terminal fragments. Together with the accompanying paper (Yamazaki, H., Chan, J., Ikura, M., Michikawa, T., and Mikoshiba, K. (2010) J. Biol. Chem. 285, 36081-36091), we demonstrate that the single aromatic residue in this region (Tyr-167 in IP₃R1 and Trp-168 in IP₃R3) plays a critical role in the coupling between ligand binding and channel gating.