Chemical and semisynthesis of modified histones

Abstract

Post-translational modifications (PTMs) of histones play critical roles in the epigenetic regulation of eukaryotic genome by directly altering the biophysical properties of chromatin or by recruiting effector proteins. The large number of PTMs and the inherent complexity in their population and signaling processes make it highly challenging to understand epigenetics-related processes. To address these challenges, accesses to homogeneously modified histones are obligatory. Over the last decade, synthetic protein chemists have been devising novel synthetic tools and applying state-of-the-art chemoselective ligation strategies to prepare precious materials useful in answering fundamental questions in this area. In this short review, we cover some of the recent breakthroughs in these directions in particular the synthesis and semi-synthesis of modified histones and their use to unravel the mysteries of epigenetics. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Advances on structural mechanisms of ubiquitinated nucleosome complexes

“…化学合成修饰组蛋白的方法包含三类: 半胱氨酸 参与的蛋白修饰过程、非天然氨基酸替换、蛋白质交 联 [41] . 化学合成蛋白主要分为全合成与半合成两种方 法 [42] . 蛋白全合成需要将目标蛋白分为若干个比较短 的多肽链, 再将固相合成的这些多肽链化学连接成一 条蛋白 [43~48] .…”

Total Chemical Synthesis of Modified Histones

“…The study of complicated PTMs as well as their biological function and mechanism of action raised the “histone code” hypothesis (Strahl and Allis, 2000 ; Jenuwein and Allis, 2001 ), which has profound effects on the cognition of DNA-related processes and treatments of diseases such as cancer (Chi et al, 2010 ; Maze et al, 2014 ). However, due to the diversity of PTM sites, complexity of PTM types as well as the synergies of multiple PTMs, it remains largely unknown how these PTMs are mediating epigenetic regulation (Maity et al, 2016 ). To elucidate the biochemical and structural mechanisms of various PTMs as well as how these PTMs mediate epigenetic regulation, it is essential to obtain sufficient amount of homogeneously modified histones with site-specific PTMs (Maity et al, 2016 ).…”

“…However, due to the diversity of PTM sites, complexity of PTM types as well as the synergies of multiple PTMs, it remains largely unknown how these PTMs are mediating epigenetic regulation (Maity et al, 2016 ). To elucidate the biochemical and structural mechanisms of various PTMs as well as how these PTMs mediate epigenetic regulation, it is essential to obtain sufficient amount of homogeneously modified histones with site-specific PTMs (Maity et al, 2016 ).…”

Synthetic and semi-synthetic strategies to study ubiquitin signaling

“…In addition, ubiquitin-based DUB probes and fluorescent ubiquitin-based enzyme substrates have seen an enormous boost, producing ubiquitin-based tools in all sorts of different flavors [7]. Two other highly investigated areas of synthetic and semi-synthetic ubiquitin-conjugate research focus on ubiquitinated histones [8,9] and ubiquitinated asynuclein [10,11]. We will briefly introduce the current synthetic and semi-synthetic methods that can be applied to generate ubiquitin and Ub-based tools and then focus on three other rapidly developing areas.…”