Cracking the Floral Quartet Code: How Do Multimers of MIKC^C-Type MADS-Domain Transcription Factors Recognize Their...

MADS-domain transcription factors (MTFs) are involved in the control of many important processes in eukaryotes. They are defined by the presence of a unique and highly conserved DNA-binding domain, the MADS domain. MTFs bind to double-stranded DNA as dimers and recognize specific sequences termed CArG boxes (such as 5'-CC(A/T)₆GG-3') and similar sequences that occur hundreds of thousands of times in a typical flowering plant genome. The number of MTF-encoding genes increased by around two orders of magnitude during land plant evolution, resulting in roughly 100 genes in flowering plant genomes. This raises the question as to how dozens of different but highly similar MTFs accurately recognize the cis-regulatory elements of diverse target genes when the core binding sequence (CArG box) occurs at such a high frequency. Besides the usual processes, such as the base and shape readout of individual DNA sequences by dimers of MTFs, an important sublineage of MTFs in plants, termed MIKC^C-type MTFs (M^C-MTFs), has evolved an additional mechanism to increase the accurate recognition of target genes: the formation of heterotetramers of closely related proteins that bind to two CArG boxes on the same DNA strand involving DNA looping. M^C-MTFs control important developmental processes in flowering plants, ranging from root and shoot to flower, fruit and seed development. The way in which M^C-MTFs bind to DNA and select their target genes is hence not only of high biological interest, but also of great agronomic and economic importance. In this article, we review the interplay of the different mechanisms of target gene recognition, from the ordinary (base readout) via the extravagant (shape readout) to the idiosyncratic (recognition of the distance and orientation of two CArG boxes by heterotetramers of M^C-MTFs). A special focus of our review is on the structural prerequisites of M^C-MTFs that enable the specific recognition of target genes.