Total Chemical Synthesis of ISGylated-Ubiquitin Hybrid Chain Assisted by Acetamidomethyl Derivatives with Dual Functions.,Bioconjugate Chemistry

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Total Chemical Synthesis of ISGylated-Ubiquitin Hybrid Chain Assisted by Acetamidomethyl Derivatives with Dual Functions.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-02-18 , DOI: 10.1021/acs.bioconjchem.0c00026
Emad Eid ₁ , Gábor N Boross ₁ , Hao Sun ₁ , Muna Msallam ₁ , Sumeet K Singh ₁ , Ashraf Brik ₁

Affiliation

Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like modifiers (ULM) family, which adopts a β-grasp fold domain(s) similar to ubiquitin (Ub) with only minor sequence homology. ISG15 consists of two Ub-like domains and aids the immune system in neutralizing infections by numerous pathogens and plays an important role in defending cells against many viruses including influenza A. Recently, Ub was found to be a substrate for ISG15, which can be ISGylated on Lys29 and Lys48, while the former is more dominant. The discovery of such hybrid ISG15-Ub chains brought forward various fundamental questions regarding the nature and effect of this conjugation. To further investigate the role of hybrid ISG15-Ub chains, the pure homogeneous material of these chains is needed in workable quantities. By applying advanced chemical strategies for protein synthesis, we report the total chemical synthesis of a 231-residue ISG15-Lys29-Ub hybrid chain. During the synthesis we encountered insoluble peptide fragments, and therefore we developed a new reversible Acm based solubilizing tag to efficiently tackle this hurdle. This new Acm tag was compared with the known Arg based Acm solubilizing tag and was found to be more reliable in terms of incorporation and efficiency as demonstrated in the synthesis of the native ISG15-Ub hybrid chain.

中文翻译：

具有双功能的乙酰氨基甲基衍生物辅助的ISGylated-泛素杂合链的全化学合成。

干扰素刺激基因15（ISG15）是泛素样修饰子（ULM）家族的成员，该家族采用与泛素（Ub）类似的β抓握折叠结构域，仅具有很小的序列同源性。ISG15由两个Ub样结构域组成，可帮助免疫系统中和多种病原体的感染，并且在防御细胞抵抗包括A型流感在内的许多病毒方面起着重要作用。最近，Ub被发现是ISG15的底物，可以被ISGylated在Lys29和Lys48上，而前者则更具优势。此类杂化ISG15-Ub链的发现提出了有关这种缀合的性质和作用的各种基本问题。为了进一步研究ISG15-Ub杂合链的作用，需要这些链的纯均质材料。通过应用蛋白质合成的先进化学策略，我们报告了231个残基的ISG15-Lys29-Ub杂合链的总化学合成。在合成过程中，我们遇到了不溶性肽片段，因此我们开发了一种新的基于Acm可逆的增溶标签来有效解决这一难题。将该新的Acm标签与已知的基于Arg的Acm增溶标签进行了比较，发现在掺入和效率方面更可靠，如天然ISG15-Ub杂合链的合成所示。

更新日期：2020-02-24

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