How Do Intrinsically Disordered Viral Proteins Hijack the Cell?
How Do Intrinsically Disordered Viral Proteins Hijack the Cell?
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DOI：
10.1021/acs.biochem.8b00622
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发表时间：
2018-07-17
期刊：
影响因子：
2.9
通讯作者：
Wright PE
中科院分区：
文献类型：
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作者：
Dyson HJ;Wright PE
细胞信号转导过程依赖于本质无序蛋白 (IDP) 或蛋白区域 (IDR) 的存在，利用无序的独特属性，包括通过相同多肽与多个伙伴的相互作用介导的通路串扰，以及通过组合翻译后修饰控制信号传导。 1 无序和部分无序的蛋白质，例如细胞周期蛋白依赖性激酶抑制剂 p21、视网膜母细胞瘤肿瘤抑制蛋白 pRb 和肿瘤抑制蛋白 p53 在细胞周期调节中发挥着核心作用。病毒还利用无序蛋白质，这些蛋白质可以破坏和破坏细胞周期和正常的细胞信号传导过程。病毒是人类和其他物种癌症的确定原因。紊乱的病毒癌蛋白是癌症表型的核心；它们与细胞蛋白竞争与中央控制系统的结合。病毒诱发癌症的直接原因之一是无序的病毒癌蛋白与视网膜母细胞瘤蛋白 pRb 的相互作用。 2 在正常细胞周期中（图 1A），E2F 和 DP 转录因子允许细胞在第一个生长期结束时超越 G1 检查点并进入 S 期，它们与 pRb 形成复合物（图 1 B）。超过 G1 检查点的进展的正常信号是 pRb 的磷酸化，它会释放 E2F 和 DP（图 1 C）。然而，许多病毒癌蛋白破坏了这一过程，从其 pRb 复合物中释放 E2F，导致异常的细胞周期进程和不受控制的细胞增殖和癌症（图 1D）。一个有趣的谜题是，即使对于非常相似的病毒株，感染导致癌症的倾向也显着不同。例如，人类乳头状瘤病毒 (HPV) 的某些菌株具有极高的癌症风险，而其他菌株则仅引起良性乳头状瘤（疣）。 3 几乎所有宫颈癌病例都与HPV高危株感染有关；现在可以通过接种 HPV 疫苗来预防这种毁灭性疾病。是什么导致某些 HPV 毒株为高风险，而密切相关的毒株为低风险？对源自两种毒株（一种高危型 (HPV16) 和一种低危型 (HPV6b)）的 HPV E7 蛋白相互作用的比较研究表明，致癌潜力的差异与 E7 对转录激活剂 CREB 结合蛋白 (CBP) 亲和力的差异相关。 E7 蛋白是两个 98 个残基单体的二聚体，具有折叠的 C 端二聚化结构域和 N 端无序结构域，可与 pRb 的 AB 口袋结构域和 CBP 的 TAZ2 结构域结合。 HPV16的E7对TAZ2的亲和力远高于HPV6b的E7，高危E7与TAZ2和pRb形成稳定的三元复合物。这种三元复合物可能解释了高风险 E7 的高致癌潜力。在没有 E7 的情况下，pRb 和 CBP 之间不存在相互作用。然而，在三元配合物中，pRb 是
Cellular signaling processes rely on the presence of intrinsically disordered proteins (IDPs) or regions of proteins (IDRs), employing unique attributes of disorder that include pathway cross-talk, brokered by interactions of the same polypeptide with multiple partners, and control of signaling by combinatorial post-translational modifications. 1 Disordered and partly-disordered proteins such as cyclindependent kinase inhibitor p21, retinoblastoma tumor suppressor protein pRb, and tumor suppressor p53 play central roles in regulation of the cell cycle. Viruses also employ disordered proteins, which serve to disrupt and subvert the cell cycle and normal cellular signaling processes. Viruses are an established cause of cancer in humans and other species. Disordered viral oncoproteins are central to the cancer phenotype; they compete with cellular proteins for binding to central control systems.One of the proximate causes of virus-induced cancer is the interaction of disordered viral oncoproteins with retinoblastoma protein pRb. 2 In the normal cell cycle (Figure 1A), the E2F and DP transcription factors, which allow the cell to progress beyond the G1 checkpoint at the end of the first growth phase and into the S phase, are sequestered in complex with pRb (Figure 1 B). The normal signal for progression beyond the G1 checkpoint is the phosphorylation of pRb, which releases E2F and DP (Figure 1 C). However, many viral oncoproteins subvert this process, releasing E2F from its pRb complex and leading to aberrant cell cycle progression and uncontrolled cell proliferation and cancer (Figure 1 D). One intriguing puzzle is that even for very similar viral strains, the tendency of infection to lead to cancer differs markedly. For example, some strains of the human papilloma virus (HPV) have an extremely high cancer risk, while others cause only benign papillomas (warts). 3 Nearly all cases of cervical cancer are related to infection with high-risk strains of HPV; this devastating disease can now be prevented by vaccination against HPV. What makes some strains of HPV high-risk while closely related strains are low risk? Comparative studies of the interactions of the E7 protein of HPV derived from two strains, one high-risk (HPV16) and one low-risk (HPV6b), 4 showed that the difference in oncogenic potential is correlated with a difference in the E7 affinity for the transcriptional activator CREB-binding protein (CBP). The E7 protein is a dimer of two 98-residue monomers, with a folded C-terminal dimerization domain and an N-terminal disordered domain that binds to the A− B pocket domain of pRb and to the TAZ2 domain of CBP. The affinity of E7 from HPV16 for TAZ2 is much higher than that of HPV6b E7, and high-risk E7 forms a stable ternary complex with TAZ2 and pRb. This ternary complex likely explains the high oncogenic potential of highrisk E7. In the absence of E7, there is no interaction between pRb and CBP. However, in the ternary complex, the pRb is
影响因子：
3.7
作者：
Oh, Kwang-Jin;Kalinina, Anna;Bagchi, Srilata
通讯作者：
Bagchi, Srilata
影响因子：
5.6
作者：
Jansma, Ariane L.;Martinez-Yamout, Maria A.;Liao, Rong;Sun, Peiqing;Dyson, H. Jane;Wright, Peter E.
通讯作者：
Wright, Peter E.
细胞信号传导和调节中本质上无序的蛋白质。
DOI：
10.1038/nrm3920
发表时间：
2015-01
期刊：
Nature reviews. Molecular cell biology
影响因子：
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