Structural basis of 3′-end poly(A) RNA recognition by LARP1
Bibliographic record
Abstract
3' RNA exonucleases, 3' poly(A) protection, mRNA stabilization La-related proteins (LARPs) comprise a family of RNA-binding proteins involved in a wide range of posttranscriptional regulatory activities [1].The ancestral LARP3 is the long-studied nuclear La protein that specifically binds the oligo(U) 3'ends of nascent RNA polymerase III (Pol III) transcripts and protects these from digestion by 3' exonucleases.LARPs share a unique tandem of two RNA-binding domains, La motif (LaM) and RNA recognition motif (RRM), together referred to as a La-module, but vary in member-specific regions.Prior structural studies of La-modules reveal they are pliable platforms for RNA recognition in diverse contexts [2].Recently, LARP1 and LARP4 were shown to bind and stabilize mRNA 3' poly(A), but the molecular basis of that is unclear [3,4].Here, we characterize the La-module of LARP1, which plays an important role in regulating synthesis of ribosomal proteins in response to mTOR signaling and mRNA stabilization.LARP1 has been well characterized functionally but no structural information exists for its La-module.In the present study, we use a variety of biophysical techniques to investigate the nature of the LARP1 La-module [5].Unexpectedly, we find that unlike other LARPs, the module does not contain a RRM domain.NMR and ITC studies demonstrated the stand-alone LaM domain binds RNA with submicromolar affinity and preference for A-rich sequences.Multiple highresolution crystal structures of LARP1 LaM in complex with poly(A) sequences of different length reveal the molecular basis for specificity for the RNA 3'-end and identify LaM residues Q333, Y336 and F348 as the most critical for RNA binding.Using a quantitative mRNA stabilization assay and poly(A) tail-sequencing, we demonstrate that high affinity binding by the LaM domain is critical for mRNA stabilization by LARP1.The study provides novel insights into poly(A) 3' protection activity by LARP1 via competition with deadenylases for mRNA 3' end. Figure 1.Structure of the LARP1 LaM domain with A3 RNA bound.On the right, representative electron density of the penultimate A(-2) adenine base is contoured at 1σ from RNA 2Fo-Fc omit maps.
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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".