Trends in Cell Biology
ReviewArmadillo-repeat protein functions: questions for little creatures
Section snippets
Armadillo-repeat containing proteins
Armadillo (ARM)-repeat proteins are characterised by containing a repeating ∼42 amino acid motif composed of three α-helices, which was first characterized in the Drosophila segment polarity protein Armadillo [1]. Several ARM-repeat protein crystal structures have been solved 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, demonstrating that although ARM-repeat proteins do not necessarily share a great deal of sequence identity (e.g. 9, 12), they share a related structure (Figure 1) and are evolutionarily
β-catenin/Armadillo: the prototypical ARM-repeat protein
β-catenin (Armadillo in Drosophila) is a fascinating protein with many important cellular and developmental functions. The roles of β-catenin are ‘classically’ defined: (i) as an adhesion protein and (ii) as a signalling protein, transducing extracellular signals to the nucleus to modify gene expression. β-catenin has many binding partners that mediate a diverse set of cellular functions, and the protein probably acts as a ‘hub’ on which many cellular signalling networks impinge.
β-catenin is a
Proteins related to β-catenin
Animals possess several proteins related in function to β-catenin. Vertebrate plakoglobin arose from a β-catenin gene duplication in the chordate lineage [29]; human β-catenin and plakoglobin are 69% identical. Plakoglobin substitutes for β-catenin function in some instances, but has also evolved unique functions: it is a component of actin-containing cell–cell junctions, but unlike β-catenin, it is also found in desmosomes, specialised intermediate-filament-containing junctions that protect
β-catenin-like proteins outside the animal kingdom
Do proteins with the same functions as β-catenin exist outside multicellular animals? Many proteins and protein domains associated with animal cell–cell adhesion are present widely throughout eukaryotes, including in unicells [46], so this seems a reasonable question to pose. Indeed, there are some candidate proteins that have some level of shared sequence identity with β-catenin.
The Vac8p protein [47] in the unicellular yeast Saccharomyces cerevisiae (Figure 2) is 22% identical to human
Other ARM-repeat proteins and the cytoskeleton
The cytoskeleton is a fundamental component of all eukaryotic cells. As described above, animal β-catenin and p120 and yeast Vac8p all associate with actin, microtubules or both. In the next sections we focus on ARM-repeat proteins with putative homologues throughout the tree of life (Figure 2, Figure 3), which could have conserved cytoskeletal functions awaiting discovery in a variety of important unicellular eukaryotes.
ARM-repeat proteins in protein degradation
A cellular function well-served by ARM-proteins is that of targeted ubiquitination and subsequent degradation of proteins. Many ARM-repeat proteins act as E3 ubiquitin ligases, which interact with, and transfer ubiquitin directly to, a target protein [54]. ARM-repeat-containing ubiquitin ligases are most prevalent in land plants and have been reviewed elsewhere 94, 95; (Box 3). As mentioned previously, Aardvark and Arabidillo proteins both contain F-boxes (Figure 3), although whether they are
New research avenues?
Our searches identify some ARM-repeat proteins about which relatively little is known, which show cross-kingdom conservation of domain combinations, suggesting that these protein families have important functions that should be the target of further analysis in a variety of species.
ARM-repeat proteins: future directions and open questions
ARM-repeat proteins are found throughout eukaryotes and are evolutionarily ancient (Box 1). The versatile ARM-repeat structure enables diverse essential cellular functions. The recent and ongoing sequencing of genomes from throughout the eukaryotic tree of life means that it is timely for us to extend our functional studies of these exciting proteins to new systems in addition to the animals, fungi and plants where the majority of ARM-protein characterisation has taken place so far. This will
Acknowledgements
We thank Tony Holder for useful discussions and Laura Moody and Younousse Saidi for critical reading of the manuscript. We acknowledge the Leverhulme Trust (Research Project Grant F/00094/BA - JC) and the Medical Research Council (MRC Investigator grant G0900109/90687 - RT) for support. We thank anonymous reviewers for helpful comments. We apologise to those whose work is only cited in review form owing to lack of space.
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