Ubiquitin chain elongation requires E3-dependent tracking of the emerging conjugate.

Protein modification with ubiquitin chains is an essential signaling event catalyzed by E3 ubiquitin ligases. Most human E3s contain a signature RING domain that recruits a ubiquitin-charged E2 and a separate domain for substrate recognition. How RING-E3s can build polymeric ubiquitin chains while binding substrates and E2s at defined interfaces ...
remains poorly understood. Here, we show that the RING-E3 APC/C catalyzes chain elongation by strongly increasing the affinity of its E2 for the distal acceptor ubiquitin in a growing conjugate. This function of the APC/C requires its coactivator as well as conserved residues of the E2 and ubiquitin. APC/C's ability to track the tip of an emerging conjugate is required for APC/C-substrate degradation and accurate cell division. Our results suggest that RING-E3s tether the distal ubiquitin of a growing chain in proximity to the active site of their E2s, allowing them to assemble polymeric conjugates without altering their binding to substrate or E2.
Mesh Terms:
Apc11 Subunit, Anaphase-Promoting Complex-Cyclosome, Apc2 Subunit, Anaphase-Promoting Complex-Cyclosome, Catalytic Domain, Cdc20 Proteins, Cell Cycle Checkpoints, Cell Line, Tumor, Enzyme Activation, HeLa Cells, Humans, Peptide Biosynthesis, Nucleic Acid-Independent, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Ubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitination
Mol. Cell
Date: Oct. 23, 2014
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