The structural basis of DNA target discrimination by papillomavirus E2 proteins
The structural basis of DNA target discrimination by papillomavirus E2 proteins
复制标题
DOI：
10.1074/jbc.m004541200
复制
发表时间：
2000-10-06
影响因子：
4.8
通讯作者：
Hegde, RS
中科院分区：
文献类型：
--
作者：
Kim, SS;Tam, JK;Hegde, RS
乳头瘤病毒E2蛋白调节所有乳头瘤病毒基因的转录，并且是病毒DNA复制所必需的。E2基因的破坏通常与宫颈癌的恶性程度相关，表明E2在调节肿瘤进展中具有作用。尽管来自所有特征性乳头瘤病毒的E2蛋白特异性结合相同的Ia-碱基对DNA序列，但癌症相关的人乳头瘤病毒E2蛋白显示出检测DNA柔性和固有曲率的独特能力。为了理解这种现象的结构基础，我们已经确定了人乳头瘤病毒-ls E2 DNA结合域及其具有高和低亲和力结合位点的复合物的晶体结构。E2蛋白是一个二聚体的P-桶，EB-DNA相互作用伴随着DNA的大变形，因为它符合E2表面。DNA构象和E2-DNA接触在高和低亲和力复合物中是相似的。亲和力的差异与DNA序列的柔性相关。E2蛋白从不同的乳头瘤病毒株的灵活或prebent的DNA目标的偏好与其DNA相互作用表面上的正电荷的分布，这表明静电力在识别DNA变形能力的作用。
The papillomavirus E2 proteins regulate the transcription of all papillomavirus genes and are necessary for viral DNA replication. Disruption of the E2 gene is commonly associated with malignancy in cervical carcinoma, indicating that E2 has a role in regulating tumor progression. Although the E2 proteins from all characterized papillomaviruses bind specifically to the same la-base pair DNA sequence, the cancer-associated human papillomavirus E2 proteins display a unique ability to detect DNA flexibility and intrinsic curvature. To understand the structural basis for this phenomenon, we have determined the crystal structures of the human papillomavirus-ls E2 DNA-binding domain and its complexes with high and low affinity binding sites. The E2 protein is a dimeric P-barrel and the EB-DNA interaction is accompanied by a large deformation of the DNA as it conforms to the E2 surface. DNA conformation and E2-DNA contacts are similar in both high and low affinity complexes. The differences in affinity correlate with the flexibility of the DNA sequence. Preferences of E2 proteins from different papillomavirus strains for flexible or prebent DNA targets correlate with the distribution of positive charge on their DNA interaction surfaces, suggesting a role for electrostatic forces in the recognition of DNA deformability.