InterPro domain: IPR003903

The Ubiquitin Interacting Motif (UIM), or 'LALAL-motif', is a stretch of about 20 amino acid residues, which was first described in the 26S proteasome subunit PSD4/RPN-10 that is known to recognise ubiquitin [ 1 , 2 ]. In addition, the UIM is found, often in tandem or triplet arrays, in a variety of proteins either involved in ubiquitination and ubiquitin metabolism, or known to interact with ubiquitin-like modifiers. Among the UIM proteins are two different subgroups of the UBP (ubiquitin carboxy-terminal hydrolase) family of deubiquitinating enzymes, one F-box protein, one family of HECT-containing ubiquitin-ligases (E3s) from plants, and several proteins containing ubiquitin-associated UBA and/or UBX domains [ 3 ]. In most of these proteins, the UIM occurs in multiple copies and in association with other domains such as UBA ( IPR015940 ), UBX ( IPR001012 ), ENTH, EH ( IPR000261 ), VHS ( IPR002014 ), SH3 ( IPR001452 ), HECT ( IPR000569 ), VWFA ( IPR002035 ), EF-hand calcium-binding, WD-40 ( IPR001680 ), F-box ( IPR001810 ), LIM ( IPR001781 ), protein kinase ( IPR000719 ), ankyrin ( IPR002110 ), PX ( IPR001683 ), phosphatidylinositol 3- and 4-kinase ( IPR000403 ), C2 ( IPR000008 ), OTU ( IPR003323 ), dnaJ ( IPR001623 ), RING-finger ( IPR001841 ) or FYVE-finger ( IPR017455 ). UIMs have been shown to bind ubiquitin and to serve as a specific targeting signal important for monoubiquitination. Thus, UIMs may have several functions in ubiquitin metabolism each of which may require different numbers of UIMs [ 4 , 5 , 6 ].

The UIM is unlikely to form an independent folding domain. Instead, based on the spacing of the conserved residues, the motif probably forms a short alpha-helix that can be embedded into different protein folds [ 7 ]. Some proteins known to contain an UIM are listed below:

• Eukaryotic PSD4/RPN-10/S5, a multi-ubiquitin binding subunit of the 26S proteasome.
• Vertebrate Machado-Joseph disease protein 1 (Ataxin-3), which acts as a histone-binding protein that regulates transcription; defects in Ataxin-3 cause the neurodegenerative disorder Machado-Joseph disease (MJD).
• Vertebrate epsin and epsin2.
• Vertebrate hepatocyte growth factor-regulated tyrosine kinase substrate (HRS).
• Mammalian epidermal growth factor receptor substrate 15 (EPS15), which is involved in cell growth regulation.
• Mammalian epidermal growth factor receptor substrate EPS15R.
• Drosophila melanogaster (Fruit fly) liquid facets (lqf), an epsin.
• Yeast VPS27 vacuolar sorting protein, which is required for membrane traffic to the vacuole.

1. Characterization of two polyubiquitin binding sites in the 26 S protease subunit 5a. J. Biol. Chem. 273, 5461-7
2. A ubiquitin-interacting motif conserved in components of the proteasomal and lysosomal protein degradation systems. Trends Biochem. Sci. 26, 347-50
3. From UBA to UBX: new words in the ubiquitin vocabulary. Trends Cell Biol. 12, 216-21
4. The ubiquitin-interacting motifs target the endocytic adaptor protein epsin for ubiquitination. Curr. Biol. 12, 1112-6
5. Cell biology: the ubiquitin connection. Nature 416, 381-3
6. Intensive chemotherapy with cyclophosphamide, carmustine, and etoposide followed by autologous bone marrow transplantation for relapsed Hodgkin's disease. J. Clin. Oncol. 9, 1871-9