Molecular Basis of the Isoform-specific Ligand-binding Affinity of Inositol 1,4,5-Trisphosphate Receptors
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Bibliographic record
Abstract
Three isoforms of the inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R), IP(3)R1, IP(3)R2, and IP(3)R3, have different IP(3)-binding affinities and cooperativities. Here we report that the amino-terminal 604 residues of three mouse IP(3)R types exhibited K(d) values of 49.5 +/- 10.5, 14.0 +/- 3.5, and 163.0 +/- 44.4 nm, which are close to the intrinsic IP(3)-binding affinity previously estimated from the analysis of full-length IP(3)Rs. In contrast, residues 224-604 of IP(3)R1 and IP(3)R2 and residues 225-604 of IP(3)R3, which contain the IP(3)-binding core domain but not the suppressor domain, displayed an almost identical IP(3)-binding affinity with a K(d) value of approximately 2 nm. Addition of 100-fold excess of the suppressor domain did not alter the IP(3)-binding affinity of the IP(3)-binding core domain. Artificial chimeric proteins in which the suppressor domain was fused to the IP(3)-binding core domain from different isoforms exhibited IP(3)-binding affinity significantly different from those of the proteins composed of the native combination of the suppressor domain and the IP(3)-binding core domain. Systematic mutagenesis analyses showed that amino acid residues critical for type-3 receptor-specific IP(3)-binding affinity are involved in Glu-39, Ala-41, Asp-46, Met-127, Ala-154, Thr-155, Leu-162, Trp-168, Asn-173, Asn-176, and Val-179. These results indicate that the IP(3)-binding affinity of IP(3)Rs is specifically tuned through the intramolecular attenuation of IP(3)-binding affinity of the IP(3)-binding core domain by the amino-terminal suppressor domain. Moreover, the functional diversity in ligand sensitivity among IP(3)R isoforms originates from at least the structural difference identified on the suppressor domain.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it