PCSK9 is phosphorylated by a Golgi casein kinase‐like kinase <i>ex vivo</i> and circulates as a phosphoprotein in humans
Bibliographic record
Abstract
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a secreted glycoprotein that regulates the degradation of the low-density lipoprotein receptor. Single nucleotide polymorphisms in its gene associate with both hypercholesterolemia and hypocholesterolemia, and studies have shown a significant reduction in the risk of coronary heart disease for 'loss-of-function' PCSK9 carriers. Previously, we reported that proPCSK9 undergoes autocatalytic processing of its prodomain in the endoplasmic reticulum and that its inhibitory prosegment remains associated with it following secretion. Herein, we used a combination of mass spectrometry and radiolabeling to report that PCSK9 is phosphorylated at two sites: Ser47 in its propeptide and Ser688 in its C-terminal domain. Site-directed mutagenesis suggested that a Golgi casein kinase-like kinase is responsible for PCSK9 phosphorylation, based on the consensus site, SXE/S(p). PCSK9 phosphorylation was cell-type specific and occurs physiologically because human plasma PCSK9 is phosphorylated. Interestingly, we show that the naturally occurring 'loss-of-function' variant PCSK9(R46L) exhibits significantly decreased propeptide phosphorylation in the Huh7 liver cell line by 34% (P < 0.0001). PCSK9(R46L) and the engineered, unphosphorylated variant PCSK9(E49A) are cleaved following Ser47, suggesting that phosphorylation protects the propeptide against proteolysis. Phosphorylation may therefore play an important regulatory role in PCSK9 function. These findings will be important for the future design of PCSK9 inhibitors.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| 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 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".