UBR1

UBR1 Full Name

ubiquitin protein ligase E3 component n-recognin 1

UBR1 Introduction

UBR1 is a large (~225 kDa in yeast, ~200 kDa in mammals) RING-type E3 ubiquitin ligase that acts as an N-recognin in the N-end rule pathway, a ubiquitin-dependent proteolytic system in which a protein's half-life is determined by the identity of its N-terminal residue. N-recognins bind destabilizing N-terminal residues—called N-degrons—through dedicated substrate-binding sites. Biochemical dissection of yeast Ubr1 identified three such sites: a type-1 site for basic N-termini (Arg, Lys, His), a type-2 site for bulky hydrophobic N-termini (Trp, Phe, Tyr, Leu, Ile), and a third site that recognizes an internal degron in the transcriptional repressor Cup9. The type-1 and type-2 activities can be separated by mutation, and Ubr1 binds destabilizing N-terminal peptides with low micromolar affinity while ignoring stabilizing residues such as Gly. These sites allow UBR1 to integrate multiple degron inputs into a single degradation decision.

Figure 1. Cooperative targeting by the N‑end rule pathway and the UFD pathway. (Source: Sriram SM, et al. 2011)

The molecular basis of N-degron recognition was revealed by mapping studies in mammalian cells and by crystallography. Deletion and mutagenesis localized degron binding to a ~72-residue UBR box (plus a downstream N-domain required for type-2 recognition), and structural analysis of the UBR box of human UBR1 in complex with N-degron peptides uncovered a previously unknown fold stabilized by a binuclear zinc center that forms a multispecific pocket for type-1 N-degrons. A missense mutation in UBR1 that causes Johanson-Blizzard syndrome disrupts this UBR-box fold and abolishes substrate binding, linking the structural mechanism directly to human disease. Physiologically, N-end rule substrates of UBR1 include cohesin fragments generated at the metaphase–anaphase transition and regulators of peptide import, illustrating how a single E3 couples N-terminal identity to chromosome segregation and nutrient sensing. Collectively, UBR1 shows how multiple degron inputs converge on one E3 to control diverse cellular processes.

Alternate Names for UBR1

UBR1; ubiquitin protein ligase E3 component n-recognin 1; JBS; E3 ubiquitin-protein ligase UBR1; E3a ligase; N-recognin-1; ubiquitin ligase E3 alpha-I; ubiquitin-protein ligase E3-alpha; ubiquitin-protein ligase E3-alpha-1; ubiquitin-protein ligase E3-alpha-I;

• 1. Sriram SM, et al. The N-end rule pathway: emerging functions and molecular principles of substrate recognition. Nat Rev Mol Cell Biol. 2011 Oct 21;12(11):735-47.
  2. Choi WS, et al. Structural basis for the recognition of N-end rule substrates by the UBR box of ubiquitin ligases. Nat Struct Mol Biol. 2010 Oct;17(10):1175-81.