Sequence Analysis of P4-ATPases Reveals the Structural Determinants for the Stable Monomeric P4B-ATPase Phospholipid Transporters
Bibliographic record
Abstract
ABSTRACT The P4-ATPase family of phospholipid flippases plays a critical role in maintenance of membrane asymmetry and cellular protein traffic and eukaryotic homeostasis. Several structures of these phospholipid flippases have been resolved, along with extensive biochemical characterization of the substrate transport properties. However, an essential subfamily of monomeric phospholipid flippases, the P4B-ATPases, remains to be characterized in depth. While P4B-ATPases appear to share similar lipid transport properties to their heterodimeric counterparts, the P4A-ATPases, the basis of their substrate translocation as monomers is currently unknown. In this study, we investigated the divergence of P4B-ATPases from other P-type ATPases using a structure-based analysis of sequence conservation. Our results showed conservative and non-conservative pockets and pathways in the P4B-ATPases near critical residues for the substrate transport pathway. P4B-ATPases also exhibit a unique interaction of an invariant proline near a conserved TM1-2 aromatic cluster, where dynamics simulation confirmed interactions with phospholipids and cholesterol by this conserved aromatic cluster. A critical TM6 residue was observed orienting into a conserved P4B-pathway whose function is currently unknown but a disease mutation hotspot, suggesting that P4B-ATPases exhibit novel transport and/or regulatory mechanisms. Our results provide a molecular framework for further studies on this essential subfamily of monomeric phospholipid flippases.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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) | 0.001 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".