UBA-like domain

Fig. 12.2. Alignment of some representative members of the various classes of UBA-like domains. Positions invariant or conservatively substituted in at least 40% of the sequences are shown on black and gray background, respectively. The UBA-like domain classes are...

Figure 12.4A shows the interaction of the first CUE domain of Cue2 interacting with ubiquitin, which might serve as a general model for the interaction mode of other UBA-like domains. The CUE domain binds to the Ile-44 patch of ubiquitin, in accordance with the chemical shift perturbation results of the UBA ubiquitin interaction [52], On the side of the CUE domain, residues of the first and third helix participate in this interaction surface. These residues include the Phe-Pro and Leu-Leu motifs, which had been predicted to be important for ubiquitin binding, based on comparative sequence analysis of CUE-A and CUE-B domains [62]. Positions in close contact with ubiquitin are also indicated in the alignment of Figure 12.3. The two available structures of the CUE ubiquitin complexes offer little expla-...

In this respect, the CUE domain is not a isolated case. There are a number of other domain families, each of them only defined in the bioinformatical sense, that have significant matches within established UBA or CUE domain regions. Based on this similarity and on secondary-structure predictions, it can be expected that all of those domain types assume the typical UBA-like three-helix bundle fold. However, it is not clear if all of those domains also bind to ubiquitin, or if they have evolved to different binding properties. Many of the UBA-like domain classes are unpublished. Nevertheless, they should be briefly discussed here, as they are a logical extension of the UBA/CUE paradigm. 

AriNT A novel UBA-like domain is found in certain RING-finger type proteins related to the ariadne protein of the fruit fly. Here, the AriNT domain is invariably... 

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. 

EFTsNT A UBA-like domain with a clear role outside of ubiquitin binding is found at the N-terminus of EF-Ts proteins. The relationship of this region to genuine UBA domains is well established as there is a structure of full-length EF-Ts available [67]. Nevertheless, this domain is widespread in bacteria and archaea, which obviously lack a proper ubiquitin system. The physiological role of the EFTsNT domain is rather in the binding to the elongation factor EF-Tu, which has no resemblance to ubiquitin. 

TapCT The C-terminus of the mammalian nuclear RNA export factor NXFl/2 (also known as Tap) contains a sequence region with significant similarity to UBA-like domains. This region is also found in the yeast RNA export factor Mex67. A three-dimensional structure of this domain is available and confirms its similarity to the UBA domain [68]. This UBA-like domain does not appear to bind to ubiquitin but rather to the Phe-Gly repeat motif found in a number of nu-cleoporins. The interaction surface of the UBA-like TapCT domain with a Phe-Gly-containing loop was mapped by an NMR/X-Ray combination technique and shown to be different from the ubiquitin-binding mode the Phe-Gly loop binds on the backside of the UBA-like domain and is in contact with helices a2 and a3 [68]. 

Initially, the role of the GAT domain in GGA proteins was seen in the binding of small GTPases of the Arf family, a critical step in the recruitment of clathrin to the TGN membrane [92]. However, the GAT domains of the Toml-like family do not bind to Arf. Recently, GAT domains of both protein classes were found to bind to ubiquitin and it was possible to separate the two binding sites to different subdomains of the GAT domain [91]. A number of X-ray structures of GAT domains are available [93-95], presenting the domain as an elongated three-helix bundle. Unlike the UBA-like structures, the GAT helices are almost parallel and considerably longer. As a prominent feature, the N-terminal helix is much longer than the others this N-terminal extension contains the Arf interaction site and is not conserved in the Toml-family [93]. 

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