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

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.

Incompletely synthesized nascent polypeptides resulting from ribosome stalling during translation are under surveillance by ribosome-associated quality control. Here, the authors report the molecular mechanism by which the E3 ligase Pirh2 targets the polyalanine tail of aberrant nascent chains for degradation via the C-degron pathway.