Perez-Jimenez Raul, Alonso-Caballero Alvaro, Berkovich Ronen, Franco David, Chen Ming-Wei, Richard Patricia, Badilla Carmen L, Fernandez Julio M
IKERBASQUE, Basque Foundation for Science, Bilbao, 48013, Spain.
ACS Nano. 2014 Oct 28;8(10):10313-20. doi: 10.1021/nn503557w. Epub 2014 Oct 14.
Cell-surface proteins are central for the interaction of cells with their surroundings and are also associated with numerous diseases. These molecules are exposed to mechanical forces, but the exact relation between force and the functions and pathologies associated with cell-surface proteins is unclear. An important cell-surface protein is CD4, the primary receptor of HIV-1. Here we show that mechanical force activates conformational and chemical changes on CD4 that may be important during viral attachment. We have used single-molecule force spectroscopy and analysis on HIV-1 infectivity to demonstrate that the mechanical extension of CD4 occurs in a time-dependent manner and correlates with HIV-1 infectivity. We show that Ibalizumab, a monoclonal antibody that blocks HIV-1, prevents the mechanical extension of CD4 domains 1 and 2. Furthermore, we demonstrate that thiol/disulfide exchange in CD4 requires force for exposure of cryptic disulfide bonds. This mechanical perspective provides unprecedented information that can change our understanding on how viruses interact with their hosts.
细胞表面蛋白对于细胞与其周围环境的相互作用至关重要，并且还与多种疾病相关。这些分子会受到机械力作用，但力与细胞表面蛋白相关的功能和病理之间的确切关系尚不清楚。一种重要的细胞表面蛋白是CD4，它是HIV-1的主要受体。在此我们表明，机械力会激活CD4上的构象和化学变化，这在病毒附着过程中可能很重要。我们利用单分子力谱和对HIV-1感染性的分析来证明，CD4的机械伸展以时间依赖性方式发生，并且与HIV-1感染性相关。我们表明，阻断HIV-1的单克隆抗体依巴珠单抗可阻止CD4第1和第2结构域的机械伸展。此外，我们证明CD4中的硫醇/二硫键交换需要力来暴露隐藏的二硫键。这种力学观点提供了前所未有的信息，可能会改变我们对病毒如何与宿主相互作用的理解。
