细胞 LxxLL 基序被乳头瘤病毒 E6 癌蛋白劫持的结构基础。
Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins.
机构信息
Biotechnologie et Signalisation Cellulaire UMR 7242, Ecole Supérieure de Biotechnologie de Strasbourg, Boulevard Sébastien Brant, BP 10413, F-67412 Illkirch, France.
出版信息
Science. 2013 Feb 8;339(6120):694-8. doi: 10.1126/science.1229934.
Abstract
E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses in vertebrates, including cervical cancer in humans. E6 proteins target many host proteins by specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus E6 proteins bound to LxxLL peptides from the focal adhesion protein paxillin and the ubiquitin ligase E6AP, respectively. In both E6 proteins, two zinc domains and a linker helix form a basic-hydrophobic pocket, which captures helical LxxLL motifs in a way compatible with other interaction modes. Mutational inactivation of the LxxLL binding pocket disrupts the oncogenic activities of both E6 proteins. This work reveals the structural basis of both the multifunctionality and the oncogenicity of E6 proteins.
摘要
E6 病毒癌蛋白是脊椎动物乳头瘤病毒诱导的上皮肿瘤的关键因素，包括人类的宫颈癌。E6 蛋白通过与酸性 LxxLL 基序特异性相互作用来靶向许多宿主蛋白。我们分别解析了牛（BPV1）和人（HPV16）乳头瘤病毒 E6 蛋白与黏着斑蛋白桩蛋白和泛素连接酶 E6AP 的 LxxLL 肽的晶体结构。在这两种 E6 蛋白中，两个锌指结构域和一个连接螺旋形成一个碱性疏水性口袋，以一种与其他相互作用模式兼容的方式捕获螺旋 LxxLL 基序。LxxLL 结合口袋的突变失活会破坏这两种 E6 蛋白的致癌活性。这项工作揭示了 E6 蛋白多功能性和致癌性的结构基础。
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