The CUE Domain

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 

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Fig. 12.3. Subclasses of the CUE domain family. All human and budding yeast members of the CUE family have been aligned and subjected to neighbor-joining dendrogram analysis. In proteins having multiple domains, the domain number is indicated in square...

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-...

Fig. 12.4. CUE and UIM bind to the same site terminal UIM of Vps27 [79]. In both panels, on ubiquitin. Schematic representation of (A) ubiquitin is rendered in darker colour and the ubiquitin in complex with the CUE domain of position of Lys-48 is indicated.

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. 

Fig. 4. The domain organizations of some CUE and LIP domain-containing proteins. Yeast Der3p/Hrdlp and Cuelp are proteins of the endoplasmic reticulum degradation pathway. As human autocrine motility factor receptor (AMFR) contains the same domain organization of a conceptual Der3p/Hrdlp and Cuelp fusion, it is proposed that DerSp/Hrdlp and Cuelp interact physically (Pouting, 2000). The C. elegans sequence most similar to human Tollip contains a C-terminal extension containing an F-box domain and an incomplete LIP domain. Over 190 LIP domains occur in at least 172 C. elegans hypothetical proteins, but have not been observed in other species sequences the functions of this domain remain unknown. LIP domains frequently co-occur with F-box domains and in one case (C33F10.8) a protein tyrosine phosphatase-like (FTP) domain.

Support rule-based behavior The interface should provide a consistent one-to-one mapping between constraints of the work domain and cues or signs presented on the interface. 

Ubiquitin Interaction with the Tollip C2 and CUE domains and PtdIns(3)P 124... 

Figure 3. Model of combinatorial inputs of segmental and dorsoventral cues that determine the formation of individual aniagen in the early mesoderm (see text). Abbreviations A, P A and P domains/compartments cm cardiac mesoderm fb fat body aniagen gm gonadal mesoderm aniagen dsm, Ism, vsm dorsal, lateral, and ventral somatic mesoderm, respectively vm midgut visceral mesoderm aniagen.

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