Alternative ubiquitin activation/conjugation cascades interact with N-end rule ubiquitin ligases to control degradation of RGS proteins.

Vertebrates express two enzymes for activation of ubiquitin-UBA1, which is responsible for activation of the vast majority of E2 conjugating enzymes, and UBA6, which uses the dedicated E2, USE1. However, targets and E3s for UBA6-USE1 are unknown. Here, we demonstrate that UBA6-USE1 functions with the UBR1-3 subfamily of N-recognin E3s ...
to degrade the N-end rule substrates RGS4, RGS5, and Arg (R)-GFP. This pathway functions in the cytoplasm in parallel with the UBA1-UBE2A/B-UBR2 cascade, which promotes turnover of nuclear RGS4/5 proteins and an apparently phenotypically distinct pool of cytoplasmic RGS4/5. UBR2 promotes Lys48 (K48)-specific ubiquitin discharge from, and RGS4 ubiquitylation by, both USE1 and UBE2A in vitro. This work provides insight into the machinery employed by the UBA6-USE1 cascade to promote protein turnover and suggests that the UBA6 and UBA1 pathways can function in parallel with the same E3 to degrade the same targets in a spatially distinct manner.
Mesh Terms:
Amino Acid Sequence, Animals, Consensus Sequence, HEK293 Cells, Humans, Mice, Molecular Sequence Data, NIH 3T3 Cells, Protein Structure, Tertiary, RGS Proteins, Sequence Alignment, Ubiquitin-Activating Enzymes, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitins
Mol. Cell
Date: Aug. 05, 2011
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