Probing biochemical interactions between the phage protein paratox and its binding partners in Streptococcus pyogenes
Bibliographic record
Abstract
Streptococcus pyogenes is responsible for over half a million deaths every year by causing diseases like necrotizing fasciitis and rheumatic heart disease. Streptococcal toxins that cause such diseases are encoded by prophages found in the S. pyogenes genome. The prophage encoded toxin genes are always found adjacent to a highly conserved gene termed paratox (prx). Past work by our lab discovered that Prx disrupts quorum sensing and natural competence in S. pyogenes by directly binding to the DNA binding domain (DBD) of quorum sensing receptor ComR. In doing so, Prx protects prophage DNA from being replaced by potential homologous recombination. To probe for additional Prx functions, we aimed to explore streptococcal biochemical pathways that may be regulated by Prx. Using a pull-down assay combined with mass-spectrometry, the lab previously identified SpyM3_0890 or EndoS1 and SpyM3_1246 or P1246 as potential Prx binding partners. To study the Prx partners, we purified both proteins to study their biochemical interactions with Prx. First, we show that both proteins form stable complexes with Prx in vitro. Next, an X-ray crystal structure of EndoS1 shows that it resembles the specificity (S) subunit of type I restriction modification (RM) enzymes. A cocrystal structure of an EndoS1:Prx complex revealed that Prx binds the EndoS1 at its potential DBD. P1246 is located in a cluster of phage genes that regulate DNA processing and Alpha Fold predicts that P1246 adopts a DBD-fold identical to ComR. Based on our structures we have identified a helical motif conserved in ComR, EndoS1, and P1246 that is critical for Prx interaction. This motif could serve as a different approach for pursuing more Prx interaction partners. Since both EndoS1 and P1246 are potential DNA binding proteins, Prx likely blocks their ability to interact with a specific promoter or repressor region in S. pyogenes. Overall, our study demonstrates how small phage proteins like Prx can regulate host biochemistry for the preservation of the phage.
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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".