Ubiquitin binding domaisn in endocytic proteins

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The question raised by ubiquitin acting as an internalization signal immediately suggested the existence of ubiquitin receptors playing a key role in internalization [167]. This hypothesis appeared strongly conforted by the identification of a number of ubiquitin binding domains in proteins involved in endocytosis. Two ubiquitin-binding motifs, the ubiquitin-associated (UBA) domain and the ubiquitin-interacting (UIM) motif have been identified in the past years, by bioinformatics approaches [168, 169]. The UBA domain consists of about 40 residues and was initially identified in E2s, E3s and other proteins associated with ubiquitylation [168]. It was subsequently demonstrated that several UBA-containing proteins bind proteins modified by ubiquitin, or bind ubiquitin chains (reviewed in [170]). The UIM motif is a stretch of about 20 amino acid residues that probably forms an a-helix. It was originally identified in the S5a/Rpn10 subunit of the proteasome, where it was shown to function as a receptor for ubiquitin chains [171]. A search for sequence similarities revealed the presence of UIMs, often in tandem, in a variety of proteins involved in ubiquitylation and, in trafficking [169]. Several of these UIM- or UBA-containing proteins, including Eps15, Ede1p and epsins, are involved in the endocytic pathway in yeast and mammalian cells [38, 61, 172]. The ubiquitin ligase c-Cbl also possesses a UBA domain [168], as does the yeast Swa2p, a protein required for clathrin assembly/disassembly in vivo [173]. Other ubiquitin binding domains more recently identified include the CUE, NZF and GAT domains. A number of publications have summarized our present knowledge of the biochemical and structural properties of all these domains in the presence or absence of linked ubiquitin, and the present understanding of their effect on intracellular trafficking (reviewed in [174]). We will focus below on some points relative to the role of UBA and UIM-containing proteins, a number of which are more specifically involved in the internalization process. But strikingly, very similar observations were made for ubiquitin-binding proteins involved in sorting of ubiquitylated cargoes into MVBs [3].