Insights into the recognition mechanism in the UBR box of UBR4 for its specific substrates

Abstract

The N-end rule pathway is a proteolytic system involving the destabilization of N-terminal amino acids, known as N-degrons, which are recognized by N-recognins. Dysregulation of the N-end rule pathway results in the accumulation of undesired proteins, causing various diseases. The E3 ligases of the UBR subfamily recognize and degrade N-degrons through the ubiquitin-proteasome system. Herein, we investigated UBR4, which has a distinct mechanism for recognizing type-2 N-degrons. Structural analysis revealed that the UBR box of UBR4 differs from other UBR boxes in the N-degron binding sites. It recognizes type-2 N-terminal amino acids containing an aromatic ring and type-1 N-terminal arginine through two phenylalanines on its hydrophobic surface. We also characterized the binding mechanism for the second ligand residue. This is the report on the structural basis underlying the recognition of type-2 N-degrons by the UBR box with implications for understanding the N-end rule pathway.

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity

“…The three identified A3-targeting E3 ligases, UBR5, HUWE1, and UBR4, have previously been linked to the turnover of a diverse array of substrates, thereby exerting control over numerous cellular processes 57,71,72,74,[87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105] . This suggests that these E3 ligases possess the ability to identify multiple substrate classes based on broad biochemical or biophysical characteristics.…”