Identification of dimer interactions required for the catalytic activity of the TRPM7 alpha-kinase domain
Bibliographic record
Abstract
TRPM7 (transient receptor potential melastatin) combines an ion channel domain with a C-terminal protein kinase domain that belongs to the atypical alpha-kinase family. The TRPM7 alpha-kinase domain assembles into a dimer through the exchange of an N-terminal segment that extends from residue 1551 to residue 1577 [Yamaguchi, Matsushita, Nairn and Kuriyan (2001) Mol. Cell 7, 1047-1057]. Here, we show, by analysis of truncation mutants, that residues 1553-1562 of the N-terminus are essential for kinase activity but not dimer formation. Within this 'activation sequence', site-directed mutagenesis identified Tyr-1553 and Arg-1558 as residues critical for activity. Examination of the TRPM7 kinase domain structure suggests that the activation sequence interacts with the other subunit to help position a catalytic loop that contains the invariant Asp-1765 residue. Residues 1563-1570 of the N-terminal segment are critical for dimer assembly. Mutation of Leu-1564, Ile-1568 or Phe-1570 to alanine abolished both kinase activity and dimer formation. The activity of a monomeric TRPM7 kinase domain lacking the entire N-terminal segment was rescued by a GST (glutathione transferase) fusion protein containing residues 1548-1576 of TRPM7, showing that all interactions essential for activity are provided by the N-terminal segment. Activity was also restored by GST fused to the N-terminal segment of TRPM6 (residues 1711-1740), demonstrating the feasibility of forming functional TRPM6-TRPM7 alpha-kinase domain heterodimers. It is proposed that covalent modifications or binding interactions that alter the conformation of the N-terminal exchanged segment may provide a means to regulate TRPM7 kinase activity.
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How this classification was reachedexpand
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 | 0.000 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".