Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
Cell. 2012 Mar 2;148(5):947-57. doi: 10.1016/j.cell.2012.01.045.
The redox-regulated chaperone Hsp33 protects organisms against oxidative stress that leads to protein unfolding. Activation of Hsp33 is triggered by the oxidative unfolding of its own redox-sensor domain, making Hsp33 a member of a recently discovered class of chaperones that require partial unfolding for full chaperone activity. Here we address the long-standing question of how chaperones recognize client proteins. We show that Hsp33 uses its own intrinsically disordered regions to discriminate between unfolded and partially structured folding intermediates. Binding to secondary structure elements in client proteins stabilizes Hsp33's intrinsically disordered regions, and this stabilization appears to mediate Hsp33's high affinity for structured folding intermediates. Return to nonstress conditions reduces Hsp33's disulfide bonds, which then significantly destabilizes the bound client proteins and in doing so converts them into less-structured, folding-competent client proteins of ATP-dependent foldases. We propose a model in which energy-independent chaperones use internal order-to-disorder transitions to control substrate binding and release.
氧化还原调控伴侣蛋白 Hsp33 可保护生物体免受导致蛋白质展开的氧化应激。Hsp33 的激活是由其自身氧化还原传感器结构域的展开引发的，这使其成为最近发现的一类伴侣蛋白的成员，这类伴侣蛋白需要部分展开才能发挥完全的伴侣活性。在这里，我们解决了长期存在的关于伴侣蛋白如何识别客户蛋白的问题。我们表明，Hsp33 使用其自身的固有无序区域来区分展开和部分结构折叠中间体。与客户蛋白中的二级结构元件结合稳定了 Hsp33 的固有无序区域，这种稳定似乎介导了 Hsp33 对结构折叠中间体的高亲和力。回到非应激条件下会减少 Hsp33 的二硫键，这会显著破坏结合的客户蛋白，并将其转化为具有较低结构、折叠能力的 ATP 依赖的折叠酶的客户蛋白。我们提出了一个模型，其中能量非依赖性伴侣蛋白使用内部有序到无序的转变来控制底物的结合和释放。
