Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia; ARC Centre of Excellence in Bioinformatics, Macquarie University, Sydney, NSW, Australia.
Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, Australia.
J Struct Biol. 2014 Mar;185(3):327-35. doi: 10.1016/j.jsb.2014.01.001. Epub 2014 Jan 11.
Integrin αvβ6 is an epithelially-restricted heterodimeric transmembrane glycoprotein, known to interact with the urokinase plasminogen activating receptor (uPAR), playing a critical role in cancer progression. While the X-ray crystallographic structures of segments of other integrin heterodimers are known, there is no structural information for the complete αvβ6 integrin to assess its direct interaction with uPAR. We have performed structural analysis of αvβ6·uPAR interactions using model data with docking simulations to pinpoint their interface, in accord with earlier reports of the β-propeller region of integrin α-chain interacting with uPAR. Interaction of αvβ6·uPAR was demonstrated by our previous study using immunoprecipitation coupled with proteomic analysis by mass spectrometry. Recently this interaction was validated with proximity ligation assays and peptide arrays. The data suggested that two potential peptide regions from domain II and one peptide region from domain III of uPAR, interact with αvβ6 integrin. Only the peptide region from domain III is consistent with the three-dimensional interaction site proposed in this study. The molecular basis of integrin αvβ6·uPAR binding using structural data is discussed for its implications as a potential therapeutic target in cancer management.
整合素 αvβ6 是一种上皮细胞限制性的异二聚体跨膜糖蛋白，已知与尿激酶型纤溶酶原激活受体 (uPAR) 相互作用，在癌症进展中发挥关键作用。虽然其他整合素异二聚体的部分 X 射线晶体结构是已知的，但没有完整的 αvβ6 整合素的结构信息来评估其与 uPAR 的直接相互作用。我们使用对接模拟进行了结构分析，以确定其界面，这与整合素 α 链 β 桨叶区域与 uPAR 相互作用的早期报告一致。我们之前的研究使用免疫沉淀结合质谱进行蛋白质组学分析证明了 αvβ6·uPAR 的相互作用。最近，该相互作用已通过邻近连接测定和肽阵列得到验证。数据表明，uPAR 的结构域 II 中有两个潜在的肽区域和一个肽区域与 αvβ6 整合素相互作用。只有来自结构域 III 的肽区域与本研究提出的三维相互作用位点一致。使用结构数据讨论了整合素 αvβ6·uPAR 结合的分子基础，因为它作为癌症管理中潜在治疗靶点的意义。
