The ZU5 domain is a domain of 90-110 residues present in zona occludens 1 (ZO-1) protein, in unc5-like netrin receptors and in ankyrins. The ZU5 domain is named after the mouse tight junction protein ZO-1 and the C. elegans uncoordinated protein 5 (unc-5) and related Unc5-like netrin receptors. ZU5 domains are found in eukaryotic proteins that in most cases contain a C-terminal death domain. Other domains which can be found N-terminal to a ZU5 domain are ankyrin repeats; Ig-like and TSP1 repeats; PDZ, SH3 and guanylate kinase; or leucine-rich repeats (LRR) [ (PUBMED:9126742) (PUBMED:9126743) (PUBMED:14769797) (PUBMED:15073321) ]. The ZU5 domain can function as a spectrin-binding domain in ankyrins [ (PUBMED:15262991) ], and participates in induction of apoptosis and binding of melanoma-associated antigen D1 (MAGE-D1/NRAGE) in UNC5H1-3 [ (PUBMED:12598531) ].
Family alignment:
There are 4021 ZU5 domains in 4021 proteins in SMART's nrdb database.
Click on the following links for more information.
Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing ZU5 domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with ZU5 domain is also avaliable.
Click on the protein counts, or double click on taxonomic names to display all proteins containing ZU5 domain in the selected taxonomic class.
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
The mouse rostral cerebellar malformation gene encodes an UNC-5-like protein.
Nature. 1997; 386: 838-42
Display abstract
Migration of neurons from proliferative zones to their functional sites is fundamental to the normal development of the central nervous system. Mice homozygous for the spontaneous rostral cerebellar malformation mutation (rcm(s)) or a newly identified transgenic insertion allele (rcm(tg)) exhibit cerebellar and midbrain defects, apparently as a result of abnormal neuronal migration. Laminar structure abnormalities in lateral regions of the rostral cerebellar cortex have been described in homozygous rcm(s) mice. We now demonstrate that the cerebellum of both rcm(s) and rcm(tg) homozygotes is smaller and has fewer folia than in the wild-type, ectopic cerebellar cells are present in midbrain regions by three days after birth, and there are abnormalities in postnatal cerebellar neuronal migration. We have cloned the rcm complementary DNA, which encodes a transmembrane receptor of the immunoglobulin superfamily. The sequence of the rcm protein (Rcm) is highly similar to that of UNC-5, a Caenorhabditis elegans protein that is essential for dorsal guidance of pioneer axons and for the movement of cells away from the netrin ligand, which is encoded by the unc-6 gene. As Rcm is a member of a newly described family of vertebrate homologues of UNC-5 which are netrin-binding proteins, our results indicate that UNC-5-like proteins may have a conserved function in mediating netrin-guided migration.
Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors.
Nature. 1997; 386: 833-8
Display abstract
In the developing nervous system, migrating cells and axons are guided to their targets by cues in the extracellular environment. The netrins are a family of phylogenetically conserved guidance cues that can function as diffusible attractants and repellents for different classes of cells and axons. In vertebrates, insects and nematodes, members of the DCC subfamily of the immunoglobulin superfamily have been implicated as receptors that are involved in migration towards netrin sources. The mechanisms that direct migration away from netrin sources (presumed repulsions) are less well understood. In Caenorhabditis elegans, the transmembrane protein UNC-5 (ref. 14) has been implicated in these responses, as loss of unc-5 function causes migration defects and ectopic expression of unc-5 in some neurons can redirect their axons away from a netrin source. Whether UNC-5 is a netrin receptor or simply an accessory to such a receptor has not, however, been defined. We now report the identification of two vertebrate homologues of UNC-5 which, with UNC-5 and the product of the mouse rostral cerebellar malformation gene (rcm), define a new subfamily of the immunoglobulin superfamily, and whose messenger RNAs show prominent expression in various classes of differentiating neurons. We provide evidence that these two UNC-5 homologues, as well as the rcm gene product, are netrin-binding proteins, supporting the hypothesis that UNC-5 and its relatives are netrin receptors.
UNC-5, a transmembrane protein with immunoglobulin and thrombospondin type 1 domains, guides cell and pioneer axon migrations in C. elegans.
Cell. 1992; 71: 289-99
Display abstract
The unc-5 gene is required for guiding pioneering axons and migrating cells along the body wall in C. elegans. In mutants, dorsal migrations are disrupted, but ventral and longitudinal movements are largely unaffected. The gene was tagged for molecular cloning by transposon insertions. Based on genomic and cDNA sequencing, the gene encodes UNC-5, a transmembrane protein of 919 aa. The predicted extracellular N-terminus comprises two immunoglobulin and two thrombospondin type 1 domains. Except for an SH3-like motif, the large intracellular C-terminus is novel. Mosaic analysis shows that unc-5 acts in migrating cells and pioneering neurons. We propose that UNC-5 is a transmembrane receptor expressed on the surface of motile cells and growth cones to guide dorsal movements.
Metabolism (metabolic pathways involving proteins which contain this domain)
This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with ZU5 domain which could be assigned to a KEGG orthologous group, and not all proteins containing ZU5 domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.
Crystal structure of the ankyrin binding domain of human erythroid beta spectrin (repeats 13-15) in complex with the spectrin binding domain of human erythroid ankyrin (ZU5-ANK)
Crystal structure of the ankyrin binding domain of human erythroid beta spectrin (repeats 13-15) in complex with the spectrin binding domain of human erythroid ankyrin (ZU5-ANK), EMTS derivative
