Tyr-167/Trp-168 in type 1/3 inositol 1,4,5-trisphosphate receptor mediates functional coupling between ligand binding and channel opening.
The N-terminal ∼220-amino acid region of the inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R)/Ca(2+) release channel has been referred to as the suppressor/coupling domain because it is required for both IP(3) binding suppression and IP(3)-induced channel gating. Measurements of IP(3)-induced Ca(2+) fluxes of mutagenized mouse type 1 IP(3)R (IP(3)R1) showed that the residues responsible for IP(3) binding suppression in this domain were not essential for channel opening. On the other hand, a single amino acid substitution of Tyr-167 to alanine completely impaired IP(3)-induced Ca(2+) release without reducing the IP(3) binding activity. The corresponding residue in type 3 IP(3)R (IP(3)R3), Trp-168, was also critical for channel opening. Limited trypsin digestion experiments showed that the trypsin sensitivities of the C-terminal gatekeeper domain differed markedly between the wild-type channel and the Tyr-167 mutant under the optimal conditions for channel opening. These results strongly suggest that the Tyr/Trp residue (Tyr-167 in IP(3)R1 and Trp-168 in IP(3)R3) is critical for the functional coupling between IP(3) binding and channel gating by maintaining the structural integrity of the C-terminal gatekeeper domain at least under activation gating.
Yamazaki
Haruka
H
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Chan
Jenny
J
Ikura
Mitsuhiko
M
Michikawa
Takayuki
T
Mikoshiba
Katsuhiko
K
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014357:Trypsin / Q000378:metabolism; 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; D014357:Trypsin; D002118:Calcium
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