Structural basis for the recognition and ubiquitylation of type-2 N-degron substrate by PRT1 plant N-recognin

Woo Seok Yang, Seu Ha Kim, Minsang Kim, Hejeong Shin, Juyeon Lee, Alexander Sandmann, Ohkmae K. Park, Nico Dissmeyer and Hyun Kyu Song ()
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Woo Seok Yang: Korea University
Seu Ha Kim: Korea University
Minsang Kim: Korea University
Hejeong Shin: Korea University
Juyeon Lee: Korea University
Alexander Sandmann: University of Osnabruck
Ohkmae K. Park: Korea University
Nico Dissmeyer: University of Osnabruck
Hyun Kyu Song: Korea University

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract PROTEOLYSIS1 (PRT1), an N-recognin of Arabidopsis thaliana, recognizes the N-terminal aromatic hydrophobic residue (Tyr/Phe/Trp) of its substrates and ubiquitylates them for degradation by the ubiquitin-proteasome system. Herein, we report the structures of the ZZ domain of PRT1 (PRT1ZZ) in complex with bulky hydrophobic N-degron peptides. Unlike other ZZ domains, PRT1ZZ has an unusual binding site with two hydrophobic regions. The N-terminal aromatic residues of N-degrons interact with Ile333 and Phe352 in the flexible loops, which undergo a conformational change. Notably, we identify a third residue from the N-terminus of the substrate that participates in the hydrophobic network with PRT1ZZ. Moreover, AlphaFold prediction and biochemical assays revealed that the tandem RING1 and RING2 domains of PRT1 interact intramolecularly. The dimeric RING domains in a single protein represent a unique feature among the RING-type E3 ligases. The biochemical assays using the N-terminal tyrosine-exposed substrate, BIG BROTHER, show that the intramolecular RING dimer is essential for PRT1’s robust activity. Therefore, this study expands our knowledge of the structural repertoire in the N-degron pathway and provides insights into the regulation of E3 ligases containing tandem RING domains.

Date: 2025
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DOI: 10.1038/s41467-025-63282-9

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