Multiubiquitylation by E4 enzymes: 'one size' doesn't fit all

Selective protein degradation by the 26S proteasome requires the covalent attachment of several ubiquitin molecules in the form of a multiubiquitin chain. Ubiquitylation usually involves three classes of enzymes: a ubiquitin-activating enzyme (El), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (U). However, in some cases, multiubiquitylation requires the additional activity of certain ubiquitin-chain elongation factors. Yeast UFD2 (ubiquitin fusion clegradation), for example, binds to oligoubiquitylated substrates (proteins modified by only a few ubiquitin molecules) and catalyses multiubiquitin-chain assembly in collaboration with El, E2 and E3. Enzymes possessing this specific activity have been proposed to be termed ' E4 enzymes '. Recent studies have provided accumulating evidence that has led some researchers in the field to conclude that E4, indeed, represents a distinct and novel class of enzymes.