Ubiquitin-conjugating enzymes (E2s) coordinate distinct types of ubiquitination via specific E3 ligases, to a large number of protein substrates. While many E2 enzymes need only the presence of an E3 ligase for substrate ubiquitination, a number of E2s require additional, non-canonical binding partners to specify their function. Here, we have determined the crystal structure and function of an E2/co-activator assembly, the Pex4p:Pex22p complex. The peroxisome-associated E2 enzyme Pex4p binds the peroxisomal membrane protein Pex22p through a binding site that does not overlap with any other known interaction interface in E2 enzymes. Pex22p association enhances Pex4p's ability to transfer ubiquitin to a substrate in vitro, and Pex22p binding-deficient forms of Pex4p are unable to ubiquitinate the peroxisomal import receptor Pex5p in vivo. Our data demonstrate that the Pex4p:Pex22p assembly, and not Pex4p alone, functions as the E2 enzyme required for Pex5p ubiquitination, establishing a novel mechanism of E2 enzyme regulation.

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Journal Article | Research Support, Non-U.S. Gov't

Authors

Williams C, van den Berg M, Panjikar S, Stanley WA, Distel B, Wilmanns M

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