Structure of the phosphocysteine intermediate of the phosphatase of regenerating liver PTP4A1
Bibliographic record
Abstract
Phosphatases of regenerating liver (PRL or PTP4A) are protein phosphatases implicated in cell growth, magnesium homeostasis, and cancer metastasis. During catalysis, a phosphocysteine intermediate forms, which must undergo hydrolysis to regenerate the active enzyme. In addition to dephosphorylating substrates, PRLs act as pseudo-phosphatases and bind CBS-pair domain divalent metal cation transport mediators (CNNMs) to regulate magnesium transport. In this study, we investigate the role of PRL residues in phosphocysteine hydrolysis using mutagenesis, enzyme assays, and X-ray crystallography. Loss of an aspartic acid and cysteine in the catalytic site disrupts hydrolysis and stabilizes the phosphocysteine intermediate for weeks. We use this C49S/D72A double mutant to determine the crystal structure of the cysteine-phosphorylated form of PRL1 (PTP4A1). The structure confirms that phosphocysteine sterically interferes with CNNM binding, consistent with previous biochemical studies. In vitro enzyme assays reveal the aspartic acid mutation increases the initial rate of catalysis for all three PRL paralogs while the homologous mutation in the phosphatases, PTP1B and PTPN12, disrupts catalysis. This highlights the mechanistic differences between PRLs and classical protein tyrosine phosphatases. Our findings refine our understanding of PRL catalysis and identify novel mutations for investigating PRL function in cancer and magnesium homeostasis.
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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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".