The proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically eliminated and which molecular characteristics direct them for removal are fundamental questions. We reveal a mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase uses interchangeable substrate receptors to recognize the unusual C termini of abnormal proteins (i.e., C-end degrons). C-end degrons are mostly less than ten residues in length and comprise a few indispensable residues along with some rather degenerate ones. The C-terminal end position is essential for C-end degron function. Truncated selenoproteins generated by translation errors and the USP1 N-terminal fragment from post-translational cleavage are eliminated by DesCEND. DesCEND also targets full-length proteins with naturally occurring C-end degrons. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein "ends" as indicators for protein elimination.
Salicylic acid (SA) is a plant hormone critical for pathogen resistance 1 – 3 . The NPR proteins have been identified as SA receptors 4 – 10 , although how they perceive SA and coordinate hormonal signalling remains elusive. Here we report the mapping of the SA-binding core (SBC) of Arabidopsis thaliana NPR4 and its ligand-bound crystal structure at 2.3 Å resolution. The NPR4 SBC domain, refolded with SA, adopts a unique α-helical fold, which completely buries SA in its hydrophobic core. The lack of ligand entry pathway suggests that SA binding involves a major conformational remodelling of NPR4-SBC, which is validated by HDX-MS analysis of the full-length protein and SA-induced disruption of NPR1-NPR4 interactions. We show that, despite sharing nearly identical hormone-binding residues, NPR1 displays a minimal SA-binding activity compared to NPR4. We further identify two SBC surface residues, whose mutations can alter NPR4’s SA-binding ability and interaction with NPR1. Moreover, we demonstrate that expressing a SA-hypersensitive NPR4 variant could enhance SA-mediated basal immunity without compromising effector-triggered immunity because of its intact ability to re-associate with NPR1 at high SA levels. By unveiling the structural mechanisms of SA perception, our work paves the way for future investigation on the specific roles of the NPR proteins in SA signalling and their potential for engineering plant immunity.
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