Kinetic Stability of the Flavin Semiquinone in Photolyase and Cryptochrome-DASH
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Bibliographic record
Abstract
Photolyases and cryptochromes (CRY) are structurally homologous flavoproteins with divergent functions. While photolyases repair UV-damaged DNA by photoinduced electron transfer from their FAD cofactor, CRY are involved in varied cellular processes, including light-dependent plant growth, regulation of mammalian circadian rhythm, and possibly magnetoreception. Despite their importance in Nature and human health, little is known about how they tune their FAD redox properties to achieve remarkable functional diversity. In this study, we reveal a kinetic mechanism, exploited by cyclobutane pyrimidine dimer photolyase (PL), for regulating the stability of its FAD semiquinone (sq). We find that the sq in CRY-DASH (Synechocystis) is substantially more reactive toward oxidation than in PL (Anacystis nidulans) and, using deuterium isotope and pH effects, show that rate-limiting proton transfer contributes to the exceptional kinetic stability of the PL sq. Through mutagenesis, we identify two PL-specific residues in the flavin binding pocket, Trp392 and Gly389 (Try398 and Asn395 in CRY-DASH, respectively), that ensure this kinetic stability, possibly through interactions with the adenine moiety of FAD and/or adjusting the polarity of the binding site. Significantly, these relatively distal residues have a much more profound impact than two amino acids closer to the FAD. By quantifying sq stability in a series of PL-CRY exchange mutants, our findings pave the way for investigations aimed at correlating sq stability with function in these proteins. As is being recognized with other flavoproteins, we expect that kinetic tuning of the rates of electron transfer will play a function-defining role in photolyases and cryptochromes.
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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 | 0.000 | 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 it