Article ; Online: Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10.
2023 Volume 42, Issue 9, Page(s) 113100
Abstract: ... translation are modified with C-terminal polyalanine tails ("Ala-tails") that function outside ribosomes ... evolved, either from an ancient module of bacterial provenance (Pirh2) or via tinkering of a widespread C ...
| 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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| MeSH term(s) | Humans ; Alanine/metabolism ; Binding Sites ; Proteolysis ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination ; Carrier Proteins/metabolism |
| Chemical Substances | Alanine (OF5P57N2ZX) ; RCHY1 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Carrier Proteins |
| Language | English |
| Publishing date | 2023-09-06 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2649101-1 |
| ISSN | 2211-1247 ; 2211-1247 |
| ISSN (online) | 2211-1247 |
| ISSN | 2211-1247 |
| DOI | 10.1016/j.celrep.2023.113100 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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