# Disordered N-terminus of yeast Rpl8A blocks cotranslational degradation of fused proteins in cells

- Published: 2026-11-15 03:18 UTC
- Section: Life & Health › Biology & biochemistry
- Tags: cotranslational protein degradation, intrinsically disordered region, Rpl8A, Saccharomyces cerevisiae, degron, protein stabilizer, Rps31, dihydrofolate reductase, cycloheximide chase, ribosomal protein
- URL: https://realtech.media/news/rt-3775da1410175bc8fdda8fc2_disordered_n_terminus/

**In yeast, the first 50 residues of Rpl8A act as a portable stabilizer, contrary to the view that disordered regions promote proteolysis. The effect is also reported in human cells.**

![Disordered N-terminus of yeast Rpl8A blocks cotranslational degradation of fused proteins in cells](https://realtech.media/media/2026/11/787c4b0f8f480394.jpg)
*Ajay Kumar Chaurasiya, Wikimedia Commons, CC BY-SA 4.0*

Researchers working with the yeast Saccharomyces cerevisiae showed that the first 50 amino acids of the ribosomal protein Rpl8A, an intrinsically disordered region, suppress cotranslational protein degradation (CTPD) rather than promote it, according to the paper at doi.org [1]. The authors also report that disordered N-terminal fragments act as stabilizing elements in cultured human embryonic kidney cells [1]. The result runs against the common view that unstructured regions serve as entry points for proteolysis.

## Where the degron sits

Earlier work by the same group placed the degron that directs CTPD of Rpl8A within the N-terminal 100 residues. Rpl8A is stable after synthesis, so the degron must be shielded in the mature protein. A mutant lacking C-terminal residues 201–256 is unstable posttranslationally, which suggests that the C-terminal region masks the degron [1]. Structure prediction showed that residues 1–50 are disordered, while residues 51–100 form two helices in contact with C-terminal domains, including residues 234, 236 and 237 [1].

To test each part, the authors attached the fragments to the N-terminus of mouse dihydrofolate reductase (DHFR) carrying a C-terminal HA tag, and ran a cycloheximide chase. Rpl8A 1–50-DHFRha was as stable as DHFRha, whereas Rpl8A 51–100-DHFRha was degraded rapidly, like the 1–100 fusion [1]. Transcript levels of the constructs were comparable, so the difference in protein levels was not caused by transcription [1]. The degron therefore lies in residues 51–100, not in the disordered 1–50 segment.

## A portable stabilizer

The steady-state level of Rpl8A 1–50-DHFRha was much higher than that of DHFRha. Mouse DHFR is stable posttranslationally but is degraded cotranslationally in yeast, so the added segment inhibits CTPD [1]. Its level matched that of DHFRha released from a ubiquitin-DHFR precursor, which indicates a strength similar to N-terminal ubiquitin [1].

The same held for ribosomal protein Rps31, which cells normally make as a ubiquitin fusion. Rpl8A 1–50-Rps31ha accumulated at a markedly higher level than Rps31ha made without N-terminal ubiquitin, while transcript levels were comparable [1].

Deleting residues 1–50 from Rpl8A lowered the steady-state level of Rpl8A Δ1–50ha to about 50% of Rpl8Aha. The mutant was as stable as the full-length protein during the chase and its transcript was not reduced, so the deletion did not cause posttranslational degradation [1]. The authors conclude that Rpl8A 1–50 is a stabilizer that impedes CTPD of Rpl8A and can be transplanted to other proteins placed at their N-termini [1]. All experiments were carried out in cultured cells.

## Sources

1. [doi.org](https://doi.org/10.1038/s44319-026-00991-2)
2. [bioengineer.org](https://bioengineer.org/disordered-protein-termini-suppress-cotranslational-degradation-in-yeast-and-human-cells)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-3775da1410175bc8fdda8fc2_disordered_n_terminus/