Ubiquitin-like domain

F-adjacent Transcript-10 (FAT 10) is composed of two ubiquitin-like domains and capable to mark conjugated proteins for proteasomal degradation independent of ubiquitin. FAT10 is inducible by IFN-y and TNF and induces apoptosis when over expressed. 

Sakata, E., et al.. Parkin binds the RpnlO subunit of 26S proteasomes through its ubiquitin-like domain. EMBO Rep, 2003, 4(3), 301-6. 

The central feature that defines all DUBs is that they recognize and act at the C-terminus of the ubiquitin or ubiquitin-like domain. All mature ubiquitin and ubiquitin-like proteins have a C-terminal gly-gly motif and DUB cleavage releases leaving groups attached to the carboxyl group of the C-terminal glycine. With the exception of the JAMM metalloproteases, DUB catalysis starts with the nucleophilic attack of the catalytic cysteine on the carbonyl carbon of the scissile bond to... 

Mueller, T. D. and Fbigon, J. Structural determinants for the binding of ubiquitin-like domains to the proteasome. Embo J 2003, 22, 4634-45. 

Hiyama, H. et al. Interaction of hHR23 with S5a. The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of 26S proteasome. J Biol Chem 1999, 274, 28019-25. 

When looking at the examples shown in Figure 12.1, or at the large set of proteins not shown here, two general trends are obvious (i) the ubiquitin domain tends to be localized at the extreme N-terminus, and (ii) the host protein is typically involved in the ubiquitin system. The first observation has been interpreted as an evolutionary remnant of earlier ubiquitin-fusion proteins [40]. As mentioned above, ubiquitin is typically expressed as a precursor protein, wherein the ubiquitin moiety is localized at the N -terminus and has to be liberated by dedicated ubiquitin hydrolases. It is certainly possible that many extant proteins with ubiquitin-like domains used to be alternative ubiquitin precursors but have lost their cleavability. The second observation will be discussed in more detail in Sections 12.5.1 and 12.5.2. 

From the viewpoint of bioinformatics, the second observation has turned out to be most useful. The identification of a ubiquitin-like domain in a protein makes it a good candidate for a new component of the ubiquitin regulatory system. In addi-... 

Fig. 12.1. Domain scheme of selected proteins with internal ubiquitin-like domains. Ubiquitin-like domains are indicated by black boxes. Other domains are abbreviated as follows ThiF, NAD-binding domain in ubiq-uitin activating enzymes UAct, 2nd conserved domain in ubiquitin activating enzymes ...

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. 

Obviously, not all proteins known to interact with ubiquitin or ubiquitin-like domains contain one of the professional ubiquitin-interaction domains. RptS and Rpnl, two subunits of the proteasome that bind to ubiquitin and UbLs, respectively, do not belong to any of the classes described above. Most probably, a large number of uncharacterized proteins with high affinity and specificity for ubiquitin are still waiting to be discovered. The bioinformatical tools described in the early sections of this chapter will be instrumental for this task. 

A quite mysterious finding is the occasional positional replacement of ubiquitin-binding domains by ubiquitin-like domains. Parkin in Figure 12.7 is one example, another one is the UBX domain found instead of the UIMs in the ataxin-3 protein from Plasmodium falciparum [77]. There is no reason to assume that UbL domains might have a role in ubiquitin binding. A more likely explanation would be the requirement of these proteins to look like ubiquitin , irrespective of whether ubiquitin is part of the protein itself or rather bound to it non-covalently. 

Ubiquitin-like domain of proteasome-interacting proteins contains a characteristic motif... 

Recently a variety of modifiers of ubiquitin ligases have been discovered33 1 as have ubiquitin-like domains in other proteins. These findings elucidate the complexity of the sorting of proteins and removal of improperly folded and otherwise defective proteins from the secretory pathway and return to the proteasomes in the cytosol.dd ee They also suggest important roles for ubiquitination in a broad range of metabolic controls. 

Fig. 5. Domain structure of Hsp70 co-chaperones. Individual domains/modules are represented by differendy shaded boxes. The known structural features and functions of domains are indicated. The following abbreviations for the different domains were used NLS, nuclear localization sequence TRSEEX, Thr-Arg-Ser-Glu-Glu-Xaa repeat motif Ub, ubiquitin-like domain Bag, Bag homology region WW, Trp-Trp domain TPR, tetratricopeptide repeat GGMP, Gly-Gly-Met-Pro repeat motif +/—, charged region U box, U box motif of E4 ubiquitin ligases DnaK, interaction site for DnaK 70, interaction site for Hsp70 90, interaction site for Hsp90.

---