Client–scaffold interactions suppress aggregation of a client protein in model condensates
Bibliographic record
Abstract
Many studies have shown that sequestration of client proteins into condensates locally increases their concentrations and/or modulates their conformational landscapes to promote aberrant aggregation. Far fewer examples have emerged where the proteinaceous condensed phase environment protects clients from aggregation. Here, we show that a condensate scaffolded by the C-terminal disordered region of Cell Cycle Associated Protein 1 (CAPRIN1) suppresses aggregation of the Fused in Sarcoma (FUS) RNA Recognition Motif (RRM) client, both components of stress granules. Although FUS RRM aggregation is mediated through the unfolded ensemble, comparative NMR studies of the FUS RRM outside and within the condensate establish that CAPRIN1 condensates attenuate FUS RRM aggregation despite locally increasing its concentration by twofold and significantly unfolding the domain. Regions of transient intermolecular contacts between unfolded FUS RRM protomers that could drive aggregation have been identified, including the hydrophobic segments spanning I287-I308 and G335-A369. Intermolecular NOE experiments recorded on the FUS RRM:CAPRIN1 condensate indicate that CAPRIN1 interacts with much of the unfolded FUS RRM, with regions of stronger contacts including the RRM sequences 287 IFVQ 290 , 296 VTIES 300 , 322 INLY 325 , and 351 IDWFDG 356 . These interactions collectively outcompete the homotypic contacts between unfolded FUS RRM clients driving aggregation. Our results demonstrate that condensate scaffold molecules can, in some cases, shield client interprotomer interactions, delaying or completely suppressing their aggregation.
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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 | 0.000 |
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".