Conformational selection mechanism of ASHH2 methyltransferase CW domain recognising H3K4me1 histone modification

Abstract

From simple double-stranded molecule DNA is packed in the nucleus via different intermediate structures with help of various proteins organizing a complex structure referred to as chromatin. A subunit of chromatin is a nucleosome that reminiscent a reel in which the DNA region is winded around a core of proteins which are called histones. Special feature of these histones is that their terminal tails are unstructured and protrude out of the nucleosomes. This makes them to be prone to different chemical modifications such as methylation, acetylation, phosphorylation and so on. The modifications have certain effects on the associated genomic regions, for example acetylation leads to activation of genes and methylation is a mark of silencing. The pattern of the modifications and their effects are conserved and shared among organisms and is referred as “histone code”. Regulation of genes at the level of these modifications is named epigenetic regulation. In order to maintain the histone code and allow epigenetic regulation specialized machinery is necessary. Such function is performed by various proteins that are able to recognize and modify these histone modifications. Worth mentioning that if something goes wrong with these processes it leads to development of various diseases and cancer is one of them.

The research presented in the dissertation was focusing on the mechanism that allows specific recognition of monomethylated modification of lysine at 4th position on histone H3 (H3K4me1) by CW domain of histone methyltransferase ASHH2. After structural and biophysical characterization of interaction it can be concluded that CW exists as an ensemble of fluctuating structures that sample different modifications of H3K4 until it uptakes H3K4me1 modification that pushes the conformation of the domain in such state that it has the most stable complex which is balanced by formation of additional secondary structure features and has lowest free energy.