The ubiquitin-interacting motif (UIM) was first described as a region of sequence homology to the ubiquitin binding S5a subunit of the 26S proteasome. The motif is found in a number of proteins involved in endocytosis and protein trafficking and can bind monoubiquitin as well as polyubiquitin chains. It has been suggested that UIM binding to monoubiquitylated substrates limits polyubiquitin chain assembly by blocking subsequent ubiquitin attachment to Lys48 of ubiquitin. Interestingly, several UIM domain-containing proteins are themselves ubiquitylated in UIM domain-dependent manner.