Ubiquitin-recognition Domains

Table 1. Comparison of the ubiquitination/recognition domains of human pl05 (residues 441-454) and iKBa (residues 20-39)...

Ubiquitin modification of substrates can be sensed by proteins, which serve as ubiquitin receptors. These proteins harbor domains capable of ubiquitin binding and help to translate the signal into the proper physiological response by forming signaling complexes or activating downstream effectors. So far more than 15 different ubiquitin recognition motifs have been identified. 

Two distinct structural elements play a role in the ubiquitination of a target protein (i) the E3 recognition site and (ii) the anchoring residue of the polyubiquitin chain. In most cases, it is believed, though it has been shown for only a few proteins, that the first ubiquitin moiety is transferred to an -NH2 group of an internal lysine residue in the substrate. The N-terminal domain of the target protein has attracted attention both as an E3 recognition domain and, recently, as a ubiquitination site. 

Rao, H. and Sastry, A. Recognition of specific ubiquitin conjugates is important for the proteolytic functions of the ubiquitin-associated domain proteins Dsk2 and Rad23./. Biol. Chem. 2002, 277, 11691-11695. 

The CUE domain s propensity to bind ubiquitin was a quite recent discovery, and relatively little is known about its physiological role. Nevertheless, structural work done on this domain type has been instrumental for our understanding of ubiquitin recognition in general. Two independently solved structures of different CUE domains have been reported, both in isolation and in complex with ubiquitin [64, 65]. The NMR structure of the first CUE domain of the uncharacterized budding yeast protein Cue2 shows a three-helix bundle fold resembling that of the... 

TtrapNT A further UBA-like domain is found at the N-terminus of the TNF- and TRAF-associated protein Ttrap, as well as a number of other sequences including eight other human proteins and the yeast ORF Ylrl28w. The scope of proteins harboring the TtrapNT domain resembles that of the UBA proteins. The Cezarme -like proteins combine the TtrapNT module with an OUT-type protease domain, while other proteins also contain UIM or UBX domains. Most TtrapNT proteins have an established or predicted role in the ubiquitin pathway, making it likely that TtrapNT serves as a recognition module for ubiquitin or ubiquitin-like domains. 

The F-box protein family is the largest substrate-recognition subunit family. It enables the eukaryotic cells to use the SCF E3 machinery to ubiquitinate a large number of diverse protein substrates. So far, over 70 F-box proteins have been identified in the human genome [57, 58]. F-box proteins all share an 40-amino acid F-box motif, which is usually followed by a C-terminal protein-protein interaction domain such as the WD40 repeats j5-propeller (Fbw subfamily) and /eucine-rich repeats (LRRs Fbl subfamily Figure 7.5) [59, 60]. F-box proteins interact with... 

Considering the multitude of ubiquitin domains and their cognate recognition modules, the next question to address is how cells make use of these building blocks to form the highly complex ubiquitination system. Before starting with the discussion of some prominent modular protein architectures, we should bear in mind that there are a number of other functional domains participating in this... 

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