Solution structure and amino acid residues of C‐terminal RAGE (ctRAGE) involved in binding to Dia‐1 FH1 and its signaling
Bibliographic record
Abstract
The receptor for advanced glycation end products (RAGE) is a multiligand cell surface macromolecule that binds distinct ligands implicated in diabetes and inflammation. RAGE-dependent signal transduction is critically dependent on its short cytoplasmic domain and our recent work revealed that FH1 domain of Dia-1 binds to cytoplasmic tail (ct)RAGE. However, the cytoplasmic domain structure and pathways by which RAGE signals through mDia1 have yet to be fully explored. Here we present the solution structure of RAGE cytoplasmic domain and identify the Dia1-ctRAGE interaction surface. Using in-vitro NMR binding studies, we show that two amino acids, which are part of the Dia1-ctRAGE interaction surface, R5 and Q6 of ctRAGE are essential for interactions with Dia1. To confirm the Dia1-ctRAGE interaction surface we generated the ctRAGE double mutant where residues R5 and Q6 were changed to alanine to create R5AQ6A-ctRAGE and tested the hypothesis that RAGE mediated signaling proceeds via these residues. mDia-1 FH1 domain interacts with ctRAGE and is essential for ERK, AKT, JNK activation and GSK3beta phosphorylation signaling triggered by RAGE ligands. Our findings present the ctRAGE structure and establish a novel mechanism by which an extracellular signal initiated by RAGE ligands regulates RAGE signaling in a manner requiring Dia-1.
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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 | 0.000 |
| 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 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".