A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger's CATalytic Pocket.
A Novel Regulator of Activation-Induced Cytidine Deaminase/APOBECs in Immunity and Cancer: Schrödinger's CATalytic Pocket.
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DOI：
10.3389/fimmu.2017.00351
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发表时间：
2017
影响因子：
7.3
通讯作者：
Larijani M
中科院分区：
文献类型：
--
作者：
King JJ;Larijani M
激活诱导的胞苷脱氨酶（AID）及其相关的APOBEC 3胞苷脱氨酶通过突变免疫或病毒基因来增强免疫应答。由于它们的基因组突变活性，AID/APOBECs也是肿瘤发生的驱动因素。由于高度带电的表面，广泛的非特异性蛋白质-蛋白质/核酸相互作用，多分散低聚物的形成，以及一般的不溶性，通过X射线晶体学和NMR对这些蛋白质进行结构解析一直具有挑战性。因此，几乎所有可用的AID/APOBEC结构都是突变的和/或截短的形式。在2015年，我们报告了使用计算-生物化学方法相结合的AID的功能结构。在这样做的过程中，我们描述了一种新的调节机制，这是人类DNA/RNA编辑酶的第一种。该机制涉及催化袋的动态闭合。随后的X射线和NMR研究证实了我们的发现，表明其他APOBEC 3也关闭了它们的催化口袋。在这里，我们强调催化口袋关闭作为一个新兴的和重要的调控机制的AID/APOBEC 3。我们专注于三个子主题：首先，我们提出AID/APOBEC 3的可变口袋闭合率是免疫和癌症差异活性的基础，并回顾支持证据。其次，我们讨论了动态口袋关闭作为一个永远存在的内部监管机构，在其他建议的监管机制，涉及外部结合伙伴。第三，我们比较了经典的X-射线和核磁共振方法的优点，新兴的计算生化方法，特别是AID/APOBEC 3的结构阐明。
Activation-induced cytidine deaminase (AID) and its relative APOBEC3 cytidine deaminases boost immune response by mutating immune or viral genes. Because of their genome-mutating activities, AID/APOBECs are also drivers of tumorigenesis. Due to highly charged surfaces, extensive non-specific protein–protein/nucleic acid interactions, formation of polydisperse oligomers, and general insolubility, structure elucidation of these proteins by X-ray crystallography and NMR has been challenging. Hence, almost all available AID/APOBEC structures are of mutated and/or truncated versions. In 2015, we reported a functional structure for AID using a combined computational–biochemical approach. In so doing, we described a new regulatory mechanism that is a first for human DNA/RNA-editing enzymes. This mechanism involves dynamic closure of the catalytic pocket. Subsequent X-ray and NMR studies confirmed our discovery by showing that other APOBEC3s also close their catalytic pockets. Here, we highlight catalytic pocket closure as an emerging and important regulatory mechanism of AID/APOBEC3s. We focus on three sub-topics: first, we propose that variable pocket closure rates across AID/APOBEC3s underlie differential activity in immunity and cancer and review supporting evidence. Second, we discuss dynamic pocket closure as an ever-present internal regulator, in contrast to other proposed regulatory mechanisms that involve extrinsic binding partners. Third, we compare the merits of classical approaches of X-ray and NMR, with that of emerging computational–biochemical approaches, for structural elucidation specifically for AID/APOBEC3s.