Transcription factors (TFs) play a key role in any biological system, and not surprisingly are being the centre of a continuous stream of papers. I recently covered the contrasting evidence for the role of TFs in evolution as a result of the specificity of their DNA binding domains (see post here).
On my mind today is a paper looks at TFs from a completely different angle: how can the evidence for the evolution of TFs specificity be reconciled with the observation that most mutations are deleterious? A feature that makes the reorganisation of biological networks possible is the modularity of TFs: domain swapping events can alter the regulatory network, and complementary DNA duplication/diversification events can generate new switches (reviewed here, among other places). These events are particularly favourable as they don’t require single point mutations, which are more likely to disrupt TF functionality (e.g. see the classic 4000-mutant analysis of LacI, one and two).
It seems however that things are not quite that extreme: I have myself given it a go, and rather surprisingly found that even mutations in the core inducer-binding domain of LacI can actually be introduced without significant (if any) functional loss (you can enjoy this awesome paper here). Mauris C. Nnamani and colleagues went much beyond this.
Evolution of Conditional Cooperativity Between HOXA11 and FOXO1 Though Allosteric Regulation Mauris C. Nnamani, Soumya Ganguly, Vincent J. Lynch, Laura S. Mizoue, Yingchun Tong, Heather Darling, Monika Fuxreiter, Jens Meiler, Gunter P. Wagner http://dx.doi.org/10.1101/014381
In a nutshell, what the authors show is that TFs can evolve by changing the function of existing TF complexes, i.e. by subtle changes in the dynamic behaviour that controls protein-protein interactions. Not surprisingly, both allosteric mechanisms and intrinsic disorder are invoked (and demonstrated) to be part of it.
Modularity, cooperativity and allostery all are key properties of biological systems as they provide robustness as much as they allow control (as my students know far too well). Understanding the complexity of yet another TFs pair brings us a step closer to ‘real life’ Synthetic Biology applications.