Tudor Domain

Abstract

What is the Tudor domain? The Tudor domain was first identified as a segment of approximately 60 amino acids that is present in 11 repeated units in the Drosophila protein of the same name. Drosophila tudor was first identified genetically, in a large-scale screen for maternal-effect lethal mutations that affected embryonic development. Several complementation groups of such mutations were identified, in which homozygous females produced embryos that fail to specify primordial germ cell specification, and these were named after extinct European royal families (tudor, vasa, valois, and staufen). Since that time, over 200 Tudor-domain containing proteins have been identified from essentially all varieties of eukaryotes, including plants, animals, and fungi, but not from prokaryotes. Tudor domains are related to Chromo, MBT, PWWP, and Agenet-like domains that are implicated in chromatin binding. The core Tudor domain forms a β-barrel like core structure that contains four short β-strands followed by an α-helical region (Figure 1). In different types of Tudor domain containing proteins, the core Tudor domain or domains can be flanked at the amino-terminal side with other conserved motifs. What is the function of the Tudor domain? Four types of Tudor domains can be distinguished based on their flanking sequences. The original germline type Tudor domain binds to proteins with dimethylated arginine or lysine residues. Work in mammals and Drosophila is consistent with a model that arginine methylation of Piwi-type proteins, and their consequent binding to Tudor proteins, is necessary to direct the former to a structure called the nuage, which in turn is essential for piwi-interacting RNAs (piRNAs) to silence retrotransposons in germ line cells (Figure 2). Another type of Tudor domain binds methylated histone tails, suggesting that they have a common, perhaps even universal, function of facilitating protein–protein interactions through their ability to bind methylated lysine or arginine. Thus, the Tudor domain operates as a recruitment domain in a manner analogous to the SH2 domain; however, it recognizes methylated amino acids rather than phosphotyrosine. What kinds of proteins possess Tudor domains? Tudor domain-containing proteins have been linked to chromatin regulation, pre-mRNA processing, spliceosome assembly, the RISC complex, and to germ line development through their involvement in piRNA-mediated transposon silencing. Consistent with those functions, Tudor domains can be found together in the same polypeptide as various RNA binding motifs (DEAD-box or KH-domain), chromatin-binding domains (Chromo, PHD finger), DNA-binding domains (BRIGHT), and several others. Most processes in which Tudor domain-containing proteins have been implicated involve the activity of large, supramolecular complexes, which may indicate a key role for the Tudor domain in their assembly or in regulating their stability. What role do Tudor-domain containing proteins have in germ cell specification? The Drosophila tudor gene was first recovered in a large-scale forward genetic screen that identified maternal-effect lethal mutations involved in embryonic patterning. Embryos produced by tudor mutant females usually lack several posterior segments, although even from tudor-null females a small proportion of embryos are correctly patterned and viable. The effects of tudor mutations on germ cell specification are more severe; embryos produced from females carrying most tudor alleles do not specify primordial germ cells and therefore completely lack a germ line. In flies there is no known role for tudor in male germ line development; conversely its mouse counterparts TDRD1, 2, 4, 6, 7, 8, and 9 are linked to male, and not female, germ line development. This is also true for vasa, suggesting that a primordial female-specific genetic pathway involved in germ cell development has persisted in vertebrate males, but has been lost in vertebrate oogenesis. In both mice and flies, Tudor protein accumulates in germ line specific ribonucleoprotein (RNP) complexes called nuage, polar granules, or germinal granules, and this accumulation requires the activity of Vasa, a DEAD-box helicase that may be involved in RNP remodeling. Association of Tudor in the nuage in turn is essential for recruiting Aubergine (Fig. 2), which functions in retrotransposon silencing. Is this the whole story, or does Tudor function in processes other than retrotransposon silencing? The only specific role for Tudor that has been identified thus far is its function in retrotransposon silencing described above. However, it is probable that Tudor has additional functions in germ cell development. Loss of Tud function alters the population of transposon-derived piRNAs but does not eliminate or grossly derepress any particular class, thus it is difficult to conclude that germ cells lacking Tud fail to form because of uncontrolled retrotransposon activity. Tudor may have a role in assembling or stabilizing polar granules, RNP complexes related to nuage that are specifically implicated in germ cell specification, as these structures are far fewer in number and much less electron-dense in tud mutant oocytes.