Evan Morrison
University of Colorado Denver | Anschutz Medical Campus
Denver, CO
UBR4 mediates the quality control of a novel N-degron pathway
Evan Morrison and Emma Larkin-Gero
The open reading frame does more than merely encode a linear peptide sequence; it is a reservoir of regulatory information. The very beginning of the coding region plays a dual role in influencing early translation elongation and regulating protein stability via N-degron pathways. Here, as part of our investigations into how the N-terminal amino acids regulate translation, we serendipitously uncovered a new N-degron that also revealed the complexity of these pathways. Using reporter assays, we discovered that peptides bearing tertiary arginine or lysine residues at the N-terminus were rapidly degraded in mammalian cells. We found this pathway to be mediated by METAP2, which co-translationally cleaves the N-terminal methionine of N-degron bearing substrates to initiate protein decay. We show that mutations of secondary amino acids preceding the degrons sequences are sufficient to ablate protein decay. We used CRISPR-Cas9 to knock out a family of N-recognins and found that these N-degrons are exclusively targeted by the E3 ligase UBR4, but not by UBR1 or UBR2. Together, our results characterize a new N-degron pathway, that reveals a unique role for UBR4 in mediating protein quality control.
SACNAS National Diversity in STEM Conference, Portland, OR, October 26-28, 2023
