Association of papillomavirus E6 proteins with either MAML1 or E6AP clusters E6 proteins by structure, function, and evolutionary relatedness.
Association of papillomavirus E6 proteins with either MAML1 or E6AP clusters E6 proteins by structure, function, and evolutionary relatedness.
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DOI：
10.1371/journal.ppat.1006781
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发表时间：
2017-12
期刊：
影响因子：
6.7
通讯作者：
Vande Pol SB
中科院分区：
文献类型：
--
作者：
Brimer N;Drews CM;Vande Pol SB
乳头瘤病毒E6蛋白与靶细胞蛋白上显示的LXXLL肽基序结合。α属HPV E6蛋白与细胞泛素连接酶E6AP （UBE3A）结合，通过结合E6AP显示的LXXLL肽（ELTLQELLGEE），从而刺激E6AP泛素连接酶活性。Beta、Gamma和Delta属E6蛋白在细胞转录共激活因子MAML1上结合类似的LXXLL肽（WMSDLDDLLGS），从而抑制Notch信号。我们从不同的乳头瘤病毒属中表达了45种不同的动物和人类E6蛋白，以确定E6蛋白对E6AP或MAML1的总体偏好。除了Alpha外，所有HPV属的E6蛋白优先与MAML1相互作用，而不是E6AP。在动物乳头瘤病毒中，来自某些有蹄类动物（猪的SsPV1）和鲸类动物（鼠海豚和海豚）宿主的E6蛋白通过结合和靶向E6AP的降解，在功能上类似于α属HPV。β属HPV E6蛋白与Delta、Pi、Tau、Gamma、Chi、Mu、Lambda、Iota、Dyokappa、Rho和Dyolambda E6蛋白功能聚集，结合并抑制MAML1。没有一种测试的E6蛋白在物理和功能上与MAML1和E6AP相互作用，表明进化分裂。此外，E6蛋白的相互作用不足以激活E6AP的降解，这表明针对E6AP的E6蛋白共同进化，分别获得结合和触发泛素连接酶激活。具有相似生物学功能的E6蛋白聚集在系统发育树中，具有相同的结构特征。这表明E6蛋白与MAML1或E6AP结合偏好的差异是乳头瘤病毒进化中的一个重要事件。乳头瘤病毒是一大类具有重要医学和兽医意义的病毒。本研究探讨了来自不同乳头瘤病毒属的病毒E6癌蛋白，以确定E6在细胞蛋白相互作用中的区别。E6蛋白先前被发现与一种称为E6AP的泛素连接酶相互作用，从而靶向特定的细胞蛋白进行降解，或者与MAML家族蛋白相互作用以抑制Notch信号，从而改变细胞分化。目前尚不清楚乳头瘤病毒E6蛋白的不同家族是否仅与E6AP或MAML（或可能两者都有）相互作用，E6如何区分这些相互作用，以及E6与E6AP的相互作用是否与泛素连接酶激活相耦合。我们在这里发现，测试的E6蛋白在物理和功能上都没有与E6AP和MAML1相互作用，这表明通过序列相似性分析E6蛋白聚集的进化分裂。目前，乳头瘤病毒的分类是复杂的，到目前为止已经描述了38个属。这项研究在大多数乳头瘤病毒属中建立了早期进化分裂，这些病毒编码的E6蛋白在物理和功能上与MAML相关，而与E6AP相比。这为目前描述的大多数乳头瘤病毒分为两个主要功能组提供了结构和功能基础。
Papillomavirus E6 proteins bind to LXXLL peptide motifs displayed on targeted cellular proteins. Alpha genus HPV E6 proteins associate with the cellular ubiquitin ligase E6AP (UBE3A), by binding to an LXXLL peptide (ELTLQELLGEE) displayed by E6AP, thereby stimulating E6AP ubiquitin ligase activity. Beta, Gamma, and Delta genera E6 proteins bind a similar LXXLL peptide (WMSDLDDLLGS) on the cellular transcriptional co-activator MAML1 and thereby repress Notch signaling. We expressed 45 different animal and human E6 proteins from diverse papillomavirus genera to ascertain the overall preference of E6 proteins for E6AP or MAML1. E6 proteins from all HPV genera except Alpha preferentially interacted with MAML1 over E6AP. Among animal papillomaviruses, E6 proteins from certain ungulate (SsPV1 from pigs) and cetacean (porpoises and dolphins) hosts functionally resembled Alpha genus HPV by binding and targeting the degradation of E6AP. Beta genus HPV E6 proteins functionally clustered with Delta, Pi, Tau, Gamma, Chi, Mu, Lambda, Iota, Dyokappa, Rho, and Dyolambda E6 proteins to bind and repress MAML1. None of the tested E6 proteins physically and functionally interacted with both MAML1 and E6AP, indicating an evolutionary split. Further, interaction of an E6 protein was insufficient to activate degradation of E6AP, indicating that E6 proteins that target E6AP co-evolved to separately acquire both binding and triggering of ubiquitin ligase activation. E6 proteins with similar biological function clustered together in phylogenetic trees and shared structural features. This suggests that the divergence of E6 proteins from either MAML1 or E6AP binding preference is a major event in papillomavirus evolution. Papillomaviruses are a large family of viruses with great medical and veterinary importance. This study explores the viral E6 oncoproteins from diverse papillomavirus genera to determine how E6 distinguishes in interaction between cellular proteins. E6 proteins have been previously found to interact with a ubiquitin ligase called E6AP and thereby target particular cellular proteins for degradation, or to interact with MAML family proteins to repress Notch signaling and thereby alter cellular differentiation. It has been unclear if diverse families of papillomavirus E6 proteins interact with only E6AP or MAML (or possibly both), how E6 distinguishes between these interactions, and if interaction of E6 with E6AP is coupled to ubiquitin ligase activation. We find here that none of the tested E6 proteins physically and functionally interacted with both E6AP and MAML1, indicating an evolutionary split that clustered E6 proteins by sequence similarity analysis. Currently, the categorization of papillomaviruses is complex, with thirty-eight genera so far described. This study establishes an early evolutionary split among most papillomavirus genera between those viruses that encode E6 proteins that physically and functionally associate with MAML compared to E6AP. This provides a structural and functional basis for categorizing most currently described papillomaviruses into two major functional groups.
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通讯作者：
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