Recognition of an Ala-rich C-degron by the E3 ligase Pirh2

Xiaolu Wang, Yao Li, Xiaojie Yan, Qing Yang, Bing Zhang, Ying Zhang, Xinxin Yuan, Chenhao Jiang, Dongxing Chen, Quanyan Liu, Tong Liu, Wenyi Mi, Ying Yu () and Cheng Dong ()
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Xiaolu Wang: Tianjin Medical University
Yao Li: Tianjin Medical University
Xiaojie Yan: Tianjin Medical University
Qing Yang: Tianjin Medical University
Bing Zhang: Tianjin Medical University
Ying Zhang: Tianjin Medical University
Xinxin Yuan: Tianjin Medical University
Chenhao Jiang: Tianjin Medical University
Dongxing Chen: Tianjin Medical University
Quanyan Liu: Tianjin Medical University General Hospital
Tong Liu: Second Hospital of Tianjin Medical University
Wenyi Mi: Tianjin Medical University
Ying Yu: Tianjin Medical University
Cheng Dong: Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract The ribosome-associated quality-control (RQC) pathway degrades aberrant nascent polypeptides arising from ribosome stalling during translation. In mammals, the E3 ligase Pirh2 mediates the degradation of aberrant nascent polypeptides by targeting the C-terminal polyalanine degrons (polyAla/C-degrons). Here, we present the crystal structure of Pirh2 bound to the polyAla/C-degron, which shows that the N-terminal domain and the RING domain of Pirh2 form a narrow groove encapsulating the alanine residues of the polyAla/C-degron. Affinity measurements in vitro and global protein stability assays in cells further demonstrate that Pirh2 recognizes a C-terminal A/S-X-A-A motif for substrate degradation. Taken together, our study provides the molecular basis underlying polyAla/C-degron recognition by Pirh2 and expands the substrate recognition spectrum of Pirh2.

Date: 2023
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DOI: 10.1038/s41467-023-38173-6

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