Abstract
UBR box E3 ligases, also called N-recognins, are integral components of the N-degron pathway. Representative N-recognins include UBR1, UBR2, UBR4, and UBR5, and they bind destabilizing N-terminal residues, termed N-degrons. Understanding the molecular bases of their substrate recognition and the biological impact of the clearance of their substrates on cellular signaling pathways can provide valuable insights into the regulation of these pathways. This review provides an overview of the current knowledge of the binding mechanism of UBR box N-recognin/N-degron interactions and their roles in signaling pathways linked to G-protein-coupled receptors, apoptosis, mitochondrial quality control, inflammation, and DNA damage. The targeting of these UBR box N-recognins can provide potential therapies to treat diseases such as cancer and neurodegenerative diseases.
Highlights
A variety of mechanisms regulate cellular signaling pathways
In addition to the UBR box, these proteins contain various domains and motifs seen in other E3 ubiquitin ligases such as E2 binding domains, RING, HECT, F-box, and plant homeodomain (PHD) (Figure 2)
Accumulated PINK1 recruits Parkin, an E3 ubiquitin ligase, to the target mitochondria, where it ubiquitinates substrates present in the outer mitochondrial membrane (OMM), leading to the removal of the dysfunctional mitochondria by mitophagy (Figure 9B) [108,115,116]
Summary
Jung Gi Kim 1,2,† , Ho-Chul Shin 3,† , Taewook Seo 1,2 , Laxman Nawale 1,2 , Goeun Han 1,2 , Bo Yeon Kim 1,2, *, Seung Jun Kim 2,3, * and Hyunjoo Cha-Molstad 1,2, *.
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