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© 2014 Springer Science+Business Media New York. All rights are reserved. Recruitment of transcriptional regulators and enzymes that remodel chromatin structure is controlled by a complex pattern of post-translational modifications on histones and other chromatin binding proteins. These so-called epigenetic marks specifically recruit protein interaction modules that read the complex pattern of post-translational modifications resulting in assembly of protein complexes that alter chromatin structure and regulate gene transcription. Often, several diverse reader domains are present in nuclear chromatin modifying proteins acting synergistically to recognize post-translationally modified histones. In addition to this modular set of interactions, some reader domains simultaneously recognize combination of several post-translational marks, rather than isolated modifications. Due to the complexity and the large number of marks and their combinations, reader domains have evolved as large and diverse families of interaction modules that specifically recognize combinations of acetylated and methylated lysines, methylated arginines, phosphorylated serine, threonine and tyrosine residues as well as other modifications. High throughput protein crystallography has recently contributed significantly in our understanding of the structural mechanisms that govern reader-histone tail interactions. Established parallel expression and purification of recombinant reader domains have enabled screening technologies that evaluated the substrate specificity of entire families of these protein interaction modules. In addition, dysfunction of epigenetic mechanisms such as writing, erasing and reading of post-translational marks has been associated with the development of a large variety of diseases, and reader domains have recently emerged as interesting targets for pharmaceutical intervention. Here, we will review our current knowledge of reader domain structural biology, the mechanisms of specific recognition of substrate sequences and emerging inhibitors that specifically disrupt binding of reader domains to histone tails. Due to space limitations we will limit our analysis in this chapter on reader domains that primarily recognize methylated lysine and arginine residues as well as acetyl-lysine readers of the bromodomain family.

Original publication

DOI

10.1007/978-1-4614-7931-4_11

Type

Chapter

Book title

Systems Analysis of Chromatin-Related Protein Complexes in Cancer

Publication Date

01/11/2013

Pages

211 - 225