The canine papillomavirus and gamma HPV E7 proteins use an alternative domain to bind and destabilize the retinoblastoma protein.
The canine papillomavirus and gamma HPV E7 proteins use an alternative domain to bind and destabilize the retinoblastoma protein.
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DOI：
10.1371/journal.ppat.1001089
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发表时间：
2010-09-02
期刊：
影响因子：
6.7
通讯作者：
Yuan H
中科院分区：
文献类型：
--
作者：
Wang J;Zhou D;Prabhu A;Schlegel R;Yuan H
高危型HPV E6和E7蛋白协同使原代人宫颈细胞永生化，E7蛋白可以在体外独立转化成纤维细胞，主要是由于其与视网膜母细胞瘤肿瘤抑制蛋白pRb结合并降解的能力。E7与pRb的结合是由E7的保守区2（CR2）中的保守Leu-X-Cys-X-Glu（LXCXE）基序介导的，并且该结构域对于E7/pRb缔合是必需的和充分的。在目前的研究中，我们报告说，E7蛋白的恶性相关犬乳头瘤病毒2型编码的E7蛋白，丝氨酸取代半胱氨酸的LXCXE基序。在HPV中，E7中的这种取代消除了pRb结合和降解。然而，尽管在这个关键部位的变化，犬乳头瘤病毒E7蛋白仍然绑定和降解pRb。即使完全删除犬E7的LXSXE结构域未能干扰体外和体内与pRb的结合。相反，pRb的主要结合位点映射到犬E7的C-末端结构域。最后，虽然HPV E7的CR 1和CR2结构域足以降解pRb，但犬E7的C-末端区域也是pRb降解所需的。HPV基因组序列的筛选显示犬E7蛋白的LXSXE基序也存在于γ HPV中，并且我们证明γ HPV-4 E7蛋白也以类似的方式结合pRb。因此，看来2型犬PV和γ型HPV不仅在组织特异性和与免疫抑制的相关性方面具有相似的特性，而且它们的E7蛋白与pRb相互作用的机制也相似。据估计，人乳头瘤病毒（HPV）是世界上最常见的性传播感染，这些感染被认为是宫颈癌的主要原因。乳头瘤病毒癌蛋白之一E7在病毒生命周期和癌症进展中起着重要作用。在细胞中，E7与pRb（一种肿瘤抑制蛋白）结合并使其失活。对于绝大多数乳头瘤病毒，E7使用小氨基酸序列LXCXE与pRb结合。然而，我们现在已经确定了乳头瘤病毒E7蛋白，缺乏LXCXE结构域，但仍然结合和降解pRb。这种E7蛋白来源于致癌犬病毒，利用其C-末端结构域结合pRb。此外，我们发现，乳头瘤病毒的一个家族，γ型HPV，也缺乏LXCXE结构域，并使用类似的机制结合pRb。
The high-risk HPV E6 and E7 proteins cooperate to immortalize primary human cervical cells and the E7 protein can independently transform fibroblasts in vitro, primarily due to its ability to associate with and degrade the retinoblastoma tumor suppressor protein, pRb. The binding of E7 to pRb is mediated by a conserved Leu-X-Cys-X-Glu (LXCXE) motif in the conserved region 2 (CR2) of E7 and this domain is both necessary and sufficient for E7/pRb association. In the current study, we report that the E7 protein of the malignancy-associated canine papillomavirus type 2 encodes an E7 protein that has serine substituted for cysteine in the LXCXE motif. In HPV, this substitution in E7 abrogates pRb binding and degradation. However, despite variation at this critical site, the canine papillomavirus E7 protein still bound and degraded pRb. Even complete deletion of the LXSXE domain of canine E7 failed to interfere with binding to pRb in vitro and in vivo. Rather, the dominant binding site for pRb mapped to the C-terminal domain of canine E7. Finally, while the CR1 and CR2 domains of HPV E7 are sufficient for degradation of pRb, the C-terminal region of canine E7 was also required for pRb degradation. Screening of HPV genome sequences revealed that the LXSXE motif of the canine E7 protein was also present in the gamma HPVs and we demonstrate that the gamma HPV-4 E7 protein also binds pRb in a similar way. It appears, therefore, that the type 2 canine PV and gamma-type HPVs not only share similar properties with respect to tissue specificity and association with immunosuppression, but also the mechanism by which their E7 proteins interact with pRb. Human papillomaviruses (HPVs) are estimated to cause the most common sexually transmitted infection in the world, and these infections are recognized as the major cause of cervical cancer. One of the papillomavirus oncoproteins, E7, plays a major role in both the viral life cycle and progression to cancer. In cells E7 associates and inactivates pRb, a tumor suppressor protein. For the vast majority of papillomaviruses, E7 binds to pRb using a small amino acid sequence, LXCXE. However, we have now identified a papillomavirus E7 protein that lacks the LXCXE domain yet still binds and degrades pRb. This E7 protein, derived from a carcinogenic canine virus, uses its C-terminal domain to bind pRb. In addition, we discovered that a family of papillomaviruses, the gamma type HPVs, also lacks the LXCXE domain and binds pRb using a similar mechanism.
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影响因子：
5.3
作者：
HUANG, PS;PATRICK, DR;HEIMBROOK, DC
通讯作者：
HEIMBROOK, DC
DOI：
10.1016/j.biocel.2007.07.004
发表时间：
2007-01-01
影响因子：
4
作者：
Boulet, Gaele;Horvath, Caroline;Bogers, Johannes
通讯作者：
Bogers, Johannes
影响因子：
11.4
作者：
Brehm, A;Nielsen, SJ;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
5.4
作者：
Huh, KyungWon;Zhou, Xiaobo;Munger, Karl
通讯作者：
Munger, Karl
影响因子：
4.8
作者：
Liu, X;Clements, A;Marmorstein, R
通讯作者：
Marmorstein, R