The PAQosome, a novel molecular chaperoning machine for assembly of human protein complexes and networks
Bibliographic record
Abstract
The human proteome comprises the products of more than 20,000 genes, most being arranged in complexes and networks that underlie essential cell functions. The Particle for Arrangement of Quaternary structure (PAQosome), formerly known as the R2TP/Prefoldin‐like complex, is to our knowledge the only molecular chaperoning machine designed by the evolution to assemble large protein complexes and regulatory networks in humans. The human PAQosome is a 12‐subunit complex made of two multisubunit modules, namely R2TP (RUVBL1, RUVBL2, RPAP3 and PIH1D1) and Prefoldin‐like (URI1, UXT, PDRG1, PFDN2, PFDN6 and the newly discovered ASDURF), as well as two other accessory proteins (POLR2E and WDR92). Several PAQosome clients/substrates have previously been identified, including all three nuclear RNA polymerases, various small nucleolar ribonucleoproteins (snoRNPs) and small nuclear RNPs (snRNPs), all six members of the phosphatidylinositol 3‐kinase‐related kinase (PIKK) family and others. Client specificity appears to be regulated by a number of different mechanisms, including the use of alternative core PAQosome subunits that recognize different clients directly, and the action of specificity adaptors that connect the PAQosome core to specific clients. Here, we present data identifying additional PAQosome clients, some being recruited through novel mechanisms that will be discussed. For example, and similar to what has been reported for axonemal dynein complexes involved in cilium motility, we now identify cytoplasmic dynein complexes that are responsible for cargo transport along microtubules as new clients of the PAQosome. Our recent data also indicate that specific phosphorylation of PAQosome subunits is at play for recognition of an important newly‐identified client, the pre‐ribosome, which is recruited to the PAQosome along with multiple ribosome biogenesis factors. Detailed mechanisms of assembly of some client complexes as well as the effect of mutations causing genetic diseases on complex/network integrity and PAQosome function will be presented. Characterization of the PAQosome is important not only to elucidate a newly‐recognized basal mechanism of gene regulation in eukaryotes but also to explore new research avenues that can lead to development of novel therapeutic and diagnostic tools.
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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 | 0.001 | 0.001 |
| 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".