Life mimics art.
Life mimics art.
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生活模仿艺术。
DOI：
10.1038/s41422-022-00765-0
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发表时间：
2023
期刊：
影响因子：
44.1
通讯作者：
Crews,CraigM
中科院分区：
文献类型：
--
作者：
Venkatachalapathy,Muthukumaran;Crews,CraigM
沙利度胺及其衍生物来那度胺和泊马度胺是用于血液系统恶性肿瘤一线治疗的免疫调节药物。1这些IMIDS--尤其是畅销药物来那度胺(2021年约128亿美元)--在临床上对多发性骨髓瘤、骨髓增生异常综合征、淋巴瘤和滤泡性淋巴瘤有效。然而，半个世纪前，沙利度胺治疗导致数千名婴儿出现严重的出生缺陷。2到2010年，科学家发现，沙利度胺通过与Cereblon的相互作用抑制斑马鱼和鸡的肢体发育3，Cereblon是一种进化上保守的蛋白质，以其在大脑发育中的假定作用命名4，其功能障碍与轻度智力障碍有关。5Cereblon是CRL4型E3连接酶复合体的底物受体，通过用泛素标记修饰这些天然底物，从而将它们引导到内源蛋白质降解机制，从而发挥关键蛋白质的作用。沙利度胺及其衍生物的作用就像分子胶：这些IMiD药物使雷伯隆与许多非天然蛋白质底物中的一种更接近。这种相互作用导致泛素标签被添加到这些新的底物上。与天然的小脑蛋白类似，这些泛素化的非天然底物也被蛋白酶体机械降解。7 IMIDD诱导的小脑新底物的例子包括转录因子IKZF1/3、SALL4、ZFP91、ZNF692和激酶CSNK1A。8降解子是蛋白质中的一个最小的结构元素，足以通过泛素/蛋白酶体系统(UPS)靶向蛋白质进行降解。虽然有些人推测IMIDS可能模仿了自然发生的退化，但直到最近，还没有确定由ereblon识别的结构基序。最近发表在《自然》杂志上的一篇开创性文章假设沙利度胺及其衍生物可以模仿翻译后修饰(PTM)，如C-末端环酰亚胺(图1)。9他们强调，蛋白质C末端的谷氨酰胺或天冬酰胺的环化可能通过酶的作用或蛋白质老化过程中的自发环化或特定的蛋白质剪接事件而发生。因此，为了确定最小的结构退化基序，作者设计了几个模拟沙利度胺的配体，这些配体可以在功能上与细胞中的雷公藤红素结合。作为脑白蛋白结合试验的阳性对照，他们使用了之前报道的含有溴域的
Thalidomide and its derivatives lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) used in the frontline treatment of hematological malignancies. 1 These IMiDs—particularly the bestselling drug lenalidomide (~ $12.8 billion in 2021)—are clinically effective against multiple myeloma, myelodysplastic syndrome, lymphoma, and follicular lymphoma. However, half a century ago, thalidomide treatment resulted in severe birth defects in thousands of babies. 2 By 2010, scientists discovered that thalidomide curbs limb development in zebrafish and chickens through its interaction with cereblon, 3 a evolutionally conserved protein named after its presumed role in cerebral development 4 and whose dysfunction is associated with mild intellectual disability. 5Cereblon is the substrate receptor for a CRL4-type E3 ligase complex and acts as a crucial protein for efficient disposal of selected proteins 6 by decorating those native substrates with ubiquitin tags and thereby directing them to the endogenous protein degradation machinery. Thalidomide and its derivatives act like molecular glues: these IMiD drugs induce closer proximity between cereblon and one of many non-native protein substrates. This interaction results in the addition of ubiquitin tags to these neosubstrates. Similar to the native cereblon substate proteins, these ubiquitinated non-native substrates are also degraded by proteasome machinery. 7 Examples of IMiD-induced cereblon neosubstrates include the transcription factors IKZF1/3, SALL4, ZFP91, ZNF692, and the kinase CSNK1A. 8 A degron is a minimal structural element within a protein that is sufficient for targeting the protein for degradation via the Ubiquitin/Proteasome System (UPS). While some have speculated that IMiDs might mimic a naturally occurring degron, until recently the structural motif recognized by cereblon had not been identified. A recent groundbreaking article published in Nature postulated that thalidomide and its derivatives could imitate post-translational modifications (PTMs) such as C-terminal cyclic imides (Fig. 1). 9 They highlighted that cyclization of glutamine or asparagine at the C-terminus of a protein might arise either through the action of enzymes or spontaneous cyclization during protein ageing or specific protein splicing events. Thus, to identify the minimum structural degron motif, the authors designed several ligands mimicking thalidomide that could functionally engage cereblon in cells. As a positive control for cereblon engagement assay, they used the previously reported bromodomain-containing