Meyer A N, Xu Y F, Webster M K, Smith A E, Donoghue D J
Department of Chemistry/Division of Biochemistry, University of California at San Diego, La Jolla 92093-0322.
Proc Natl Acad Sci U S A. 1994 May 24;91(11):4634-8. doi: 10.1073/pnas.91.11.4634.
The E5 oncoprotein of bovine papillomavirus, only 44 amino acids long, occurs as a disulfide-bonded transmembrane dimer. This remarkable oncoprotein stimulates signal transduction through activation of the platelet-derived growth factor (PDGF) receptor, and E5 exhibits limited amino acid sequence similarity with PDGF. Results presented here suggest that a key feature of the hydrophobic transmembrane domain is an amino acid side chain that participates in interhelical hydrogen bond formation. These data are reminiscent of the activated neu oncogene, in which a point mutation in the transmembrane domain leads to ligand-independent dimerization and activation of a receptor tyrosine kinase. Significantly, the transmembrane domain of E5 can be largely replaced by the transmembrane domain from the activated neu receptor tyrosine kinase. Extensive mutagenesis defines the minimal structural features required for transformation by the E5 oncoprotein as, first, the ability to dimerize and, second, presentation of a negatively charged residue at the extracellular side of the membrane. The biological activity of E5 mutants that lack most amino acid residues similar to PDGF suggests that E5 and PDGF activate the PDGF receptor by distinct mechanisms.
牛乳头瘤病毒的E5癌蛋白仅有44个氨基酸长，以二硫键连接的跨膜二聚体形式存在。这种非凡的癌蛋白通过激活血小板衍生生长因子（PDGF）受体来刺激信号转导，并且E5与PDGF的氨基酸序列相似性有限。此处呈现的结果表明，疏水跨膜结构域的一个关键特征是参与螺旋间氢键形成的氨基酸侧链。这些数据让人联想到活化的neu癌基因，其中跨膜结构域中的一个点突变导致受体酪氨酸激酶的配体非依赖性二聚化和激活。值得注意的是，E5的跨膜结构域可在很大程度上被活化的neu受体酪氨酸激酶的跨膜结构域所取代。广泛的诱变确定了E5癌蛋白转化所需的最小结构特征，首先是二聚化的能力，其次是在膜的细胞外侧呈现带负电荷的残基。缺乏大多数与PDGF相似氨基酸残基的E5突变体的生物学活性表明，E5和PDGF通过不同机制激活PDGF受体。
