Mechanistic Studies and Engineering of Histone PTM Reader Proteins

抽象的。 组蛋白翻译后修饰（PTM），包括赖氨酸甲基化和酰化， 在染色质重塑中的作用已经得到了很好的证实，但是组蛋白PTM在疾病中的新作用，包括许多类型的疾病， 癌症，不断被发现。这个快速发展的领域需要开发新的 分子方法来探测这些PTM的生物学影响。在此，我们重点关注阅读器蛋白质 对于赖氨酸甲基化（Kme）和巴豆酰化（Kcr），因为阅读器蛋白负责感测PTM 并且Kme和Kcr都具有生物医学相关性。目标1和2使 使用全局分析策略来确定Kme和Kcr之间的不同分子识别特征 阅读器蛋白，分别将提高开发选择性抑制剂和分子探针的能力 这两类蛋白质的基因。目标3和4将利用阅读器蛋白的固有选择性来开发 工程化Kme和Kcr阅读器蛋白（eReaders和eWriters），用于传感、标记和引入 以位点选择性方式的双PTM。这一共同努力将通过提供新的见解和 研究依赖于这些PTM的生物学途径及其在疾病中的作用的新工具。

Abstract. The integral roles of histone post-translational modifications (PTMs), including lysine methylation and acylation, in chromatin remodeling is well established, but new roles of histone PTMs in diseases, including many types of cancer, are continually discovered. This rapidly evolving field necessitates the development of new molecular approaches to probe the biological impacts of these PTMs. Herein we focus on the reader proteins for lysine methylation (Kme) and crotonylation (Kcr), as reader proteins are responsible for sensing the PTM and triggering the biological outcome, and both Kme and Kcr have biomedical relevance. Aims 1 and 2 make use of global analysis strategies to determine distinct molecular recognition features across Kme and Kcr reader proteins, respectively, that will advance the ability to develop selective inhibitors and molecular probes for these two classes of proteins. Aims 3 and 4 will exploit the inherent selectivity of reader proteins to develop engineered Kme and Kcr reader proteins (eReaders and eWriters) for sensing, labeling, and introduction of dual PTMs in a site selective manner. This combined effort will advance the field by providing new insight and new tools to study the biological pathways that depend on these PTMs and their role in disease.