## 6 **YefM-YoeB and Axe-Txe: Diverse Transcriptional Control of Homologous TA Complexes**  
The YefM-YoeB system of _E. coli_ is a hybrid type II TA complex: the YoeB toxin and YefM antitoxin are related evolutionarily to RelE and Phd, respectively, whereas the usual associations are RelB-RelE and Phd-Doc [86; 87; 88]. YoeB binding to the 50S ribosomal subunit prevents the formation of the initiation complex and induces mRNA cleavage three bases downstream of the initiation codon [89]. However, the toxin's catalytic fold is concealed when it is bound to YefM thereby blocking its enzymatic activity. This interaction, which also stabilizes YefM, is crucial for ensuring that free YoeB is not available erroneously to degrade mRNA [45]. The _yefM-yoeB_ genes are transcriptionally autoregulated. YefM is the principal repressor, whereas YoeB is a repression enhancer [90]. YefM lacks a canonical DNA binding motif [45], but dual conserved arginine residues in the N-terminal segment of the protein are involved in operator recognition (Figure 2B) [46]. Free YefM sequentially recognizes adjacent long and short DNA palindromes during transcriptional repression of the _yefM-yoeB_ operon. The palindromes share core hexamer 5'-TGTACA-3' motifs, possess a centre-to-centre distance of 12-bp and overlap the _yefM-yoeB_ promoter (Figure 3). The YefM-YoeB complex binds the palindromes more avidly than free antitoxin via cooperative interactions [46; 90]. Changing the inter-palindrome spacing perturbs cooperative binding to the repeats: YefM-YoeB interaction with the long repeat is retained but binding to the short repeat is disrupted [46]. Paired hexamer motifs are frequent in _yefM-yoeB_ regulatory regions in diverse genomes suggesting that interaction of YefM-YoeB with these motifs is a conserved mode of operon transcriptional autoregulation [90]. The Axe-Txe complex encoded widely by enterococcal plasmids is homologous to YefM-YoeB [87]. Analogously, the Axe antitoxin represses the _axe-txe_ promoter weakly whereas Axe-Txe represses more strongly [91]. However, an internal promoter within _axe_ also directs expression of the downstream _txe_ toxin gene. This internal promoter is not regulated by Axe-Txe and is essential for the function of the complex as a plasmid maintenance system suggesting that it plays a vital role in setting the Axe:Txe ratio. A cryptic transcript that originates within _txe_ and a putative transcription terminator in the region 3' of the operon may be additional regulatory elements that contribute to transcriptional control of _axe-txe_[91]. The _yefM-yoeB_ operon of _Streptococcus pneumoniae_ provides another example of multilayered transcriptional control. In this case, a pair of promoters, one of which is constitutive and one of which is autoregulated by YefM-YoeB, are located upstream of the genes [92]. The interactions between the homologous YefM-YoeB and Axe-Txe complexes are species-specific. Accordingly, the complexes repress expression of the cognate promoters, but not of the non-cognate promoters, even though both operator regions are composed of a pair of inverted repeats with the same hexameric core [88]. However, a single substitution near the C-terminus which converts a Txe-specific residue to a YoeB-specific amino acid permitted neutralization of Txe by YefM _in vivo_. Moreover, the complex of wild-type YefM and mutated Txe partially corepressed the _yefM-yoeB_ promoter [88]. These data illustrate that subtle amino acid sequence changes can impose interaction specificity, including transcriptional regulation specificity, on homologous TA complexes, and provide insight into the mechanisms by which expression of multiple, homologous type II TA complexes in a single host may be regulated differentially under disparate physiological conditions [93]. Diverging from the Canonical Pattern of Type II TA Transcriptional Control: Tripartite Protein Complexes and a Toxin that Directly Binds DNA  
Certain exceptions to the general pattern of type II TA transcriptional regulation have been described.