Structural studies of inositol 1,4,5-trisphosphate receptor: coupling ligand binding to channel gating.
The three isoforms of the inositol 1,4,5-trisphosphate receptor (IP(3)R) exhibit distinct IP(3) sensitivities and cooperativities in calcium (Ca(2+)) channel function. The determinants underlying this isoform-specific channel gating mechanism have been localized to the N-terminal suppressor region of IP(3)R. We determined the 1.9 Å crystal structure of the suppressor domain from type 3 IP(3)R (IP(3)R3(SUP), amino acids 1-224) and revealed structural features contributing to isoform-specific functionality of IP(3)R by comparing it with our previously determined structure of the type 1 suppressor domain (IP(3)R1(SUP)). The molecular surface known to associate with the ligand binding domain (amino acids 224-604) showed marked differences between IP(3)R3(SUP) and IP(3)R1(SUP). Our NMR and biochemical studies showed that three spatially clustered residues (Glu-20, Tyr-167, and Ser-217 in IP(3)R1 and Glu-19, Trp-168, and Ser-218 in IP(3)R3) within the N-terminal suppressor domains of IP(3)R1(SUP) and IP(3)R3(SUP) 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 IP(3)R1 and Trp-168 in IP(3)R3) plays a critical role in the coupling between ligand binding and channel gating.
Chan
Jenny
J
Division of Signaling Biology, Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G IL7, Canada.
Yamazaki
Haruka
H
Ishiyama
Noboru
N
Seo
Min-Duk
MD
Mal
Tapas K
TK
Michikawa
Takayuki
T
Mikoshiba
Katsuhiko
K
Ikura
Mitsuhiko
M
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018360:Crystallography, X-Ray; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014364:Tryptophan / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D053496:Inositol 1,4,5-Trisphosphate Receptors; D008024:Ligands; D020033:Protein Isoforms; D014443:Tyrosine; D015544:Inositol 1,4,5-Trisphosphate; D014364:Tryptophan