ArticleCell reports2023
Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10.
Article in Cell reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 17 citations in OpenAlex.
- N-terminal formylmethionine as a degron and a specific signal in proteostasis and stress adaptation.Experimental & molecular medicine · 2026Review
- Ribosome-associated quality control and related mechanisms.Nature structural & molecular biology · 2026Review
- A near-complete map of human cytosolic degrons and their relevance for disease.Science advances · 2026Article
- Mechanical forces regulate the composition and fate of stalled nascent chains.Molecular cell · 2026Article
- Degrons: defining the rules of protein degradation.Nature reviews. Molecular cell biology · 2025Review
- Article
- Characteristics of the Kelch domain containing (KLHDC) subfamily and relationships with diseases.FEBS letters · 2025Review
- Structural basis for C-degron selectivity across KLHDCX family E3 ubiquitin ligases.Nature communications · 2024Article
- Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2.Nature communications · 2024Article
- Poly-alanine-tailing is a modifier of neurodegeneration caused by Listerin mutation.bioRxiv : the preprint server for biology · 2024Article
- Protein quality control: from molecular mechanisms to therapeutic intervention-EMBO workshop, May 21-26 2023, Srebreno, Croatia.Cell stress & chaperones · 2023Review
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9 authors at 3 institutions in 2 countries.
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Abstract
In ribosome-associated quality control (RQC), nascent polypeptides produced by interrupted translation are modified with C-terminal polyalanine tails ("Ala-tails") that function outside ribosomes to induce ubiquitylation by E3 ligases Pirh2 (p53-induced RING-H2 domain-containing) or CRL2 (Cullin-2 RING ligase2)-KLHDC10. Here, we investigate the molecular basis of Ala-tail function using biochemical and in silico approaches. We show that Pirh2 and KLHDC10 directly bind to Ala-tails and that structural predictions identify candidate Ala-tail-binding sites, which we experimentally validate. The degron-binding pockets and specific pocket residues implicated in Ala-tail recognition are conserved among Pirh2 and KLHDC10 homologs, suggesting that an important function of these ligases across eukaryotes is in targeting Ala-tailed substrates. Moreover, we establish that the two Ala-tail-binding pockets have convergently evolved, either from an ancient module of bacterial provenance (Pirh2) or via tinkering of a widespread C-degron-recognition element (KLHDC10). These results shed light on the recognition of a simple degron sequence and the evolution of Ala-tail proteolytic signaling.
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