Mechanism and evolutionary origins of alanine-tail C-degron recognition by E3 ligases Pirh2 and CRL2-KLHDC10.
Ala-tail
C-end degron
CP: Molecular biology
E3 ubiquitin ligase
KLHDC10
Pirh2
polyalanine
protein degradation
protein quality control
protein-protein interaction
structure prediction
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
26 09 2023
26 09 2023
Historique:
received:
20
03
2023
revised:
11
07
2023
accepted:
22
08
2023
medline:
5
10
2023
pubmed:
7
9
2023
entrez:
7
9
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37676773
pii: S2211-1247(23)01111-7
doi: 10.1016/j.celrep.2023.113100
pmc: PMC10591846
mid: NIHMS1933911
pii:
doi:
Substances chimiques
Alanine
OF5P57N2ZX
RCHY1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Carrier Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
113100Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102414
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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