A Structure-Based Analysis of the Evolution of Transcription Factors of the FNR/CRP Family

The X-ray structural analysis of the N-terminal domain cavity from eleven tran-scription regulators of the FNR/CRP family (TFs) has shown several significant trends: (i) The conservancy of effector-binding Phosphate Binding Cassette features in three TFs suggests a closer connection among them than the one proposed based on amino acid sequences. (ii) The allosteric TFs display three clearly different activation mechanisms, which most likely evolved independently. (iii) There are also several non-allosteric TFs which do not bind any ligand; instead, the “allosteric” cavity is partially filled with buried salt bridges, (which is also the case for two allosteric apo TFs). These observations suggest that the non-allosteric TFs evolved from an allosteric counterpart and used salt bridges to fill the formally polar ligand-binding cavity. (iv) A comparison of the allosteric mecha-nisms and the nature of the effectors suggests possible evolutionary relationships among the relevant TFs. (v) O2-sensing TFs share some residues in the relevant N-terminal domain cavity and could have had an already non-allosteric common ancestor. There is a connection between some FNR/CRP TFs and N2 fixation and O2 metabolism; both gases were already metabolized by ancestors of cyanobacteria, over three billion years (3 Ga) ago.