UBE2S drives elongation of K11-linked ubiquitin chains by the Anaphase-Promoting Complex

• DOI: 10.1073/pnas.0912802107
• Publication Date: 2010-01-07T03:37:14Z
• Authors: Tao Wu; Yifat Merbl; Ying Huo; Jennifer L. Gallop; Amit Tzur; Marc W. Kirschner
• Keywords: 0301 basic medicine; Ubiquitin; Lysine; Cell Cycle; Ubiquitin-Protein Ligase Complexes; Anaphase-Promoting Complex-Cyclosome; Neoplasm Proteins; Substrate Specificity; Securin; 03 medical and health sciences; Mutation; Ubiquitin-Conjugating Enzymes; Biocatalysis; Humans; HeLa Cells; Protein Binding

The Anaphase-Promoting Complex (APC) is an E3 ubiquitin ligase that regulates mitosis and G1 by sequentially targeting cell-cycle regulators for ubiquitination and proteasomal degradation. The mechanism of ubiquitin chain formation by APC and the resultant chain topology remains controversial. By using a single-lysine APC substrate to dissect the topology of ubiquitinated substrates, we find that APC-catalyzed ubiquitination has an intrinsic preference for the K11 linkage of ubiquitin that is essential for substrate degradation. K11 specificity is determined by an E2 enzyme, UBE2S/E2-EPF, that elongates ubiquitin chains after the substrates are pre-ubiquitinated by UbcH10 or UbcH5. UBE2S copurifies with APC; dominant-negative Ube2S slows down APC substrate degradation in functional cell-cycle extracts. We propose that Ube2S is a critical, unique component of the APC ubiquitination pathway.