Phosphodependent helix switches in cellular signalling

细胞必须能够对人体内的变化做出反应。它们生长、分裂、改变形状，有时甚至会根据身体的需要而死亡。组成一个细胞的数百万个单独的分子对细胞的反应做出贡献，它们的单独行动通过一个复杂的细胞信息系统进行协调。最常见的信息类型之一是蛋白质的化学修饰，它的存在可能会影响蛋白质的位置、稳定性或活性。这种修饰也可以被其他蛋白质检测到，然后这些蛋白质就可以传递信息。类似于书面信息，进行修改的蛋白质被称为“写入者”，而检测到修改的蛋白质被称为“读取者”。也许最常见的修饰是磷酸化，它是由一种名为激酶的蛋白质家族撰写的，在人类中有500多种。磷酸化通常用于传递细胞准备繁殖的信息，并在细胞即将分裂时达到顶峰。已知有几种不同的阅读器蛋白可以阅读磷酸化信息。它们识别磷酸基团的形状和电荷，以及它周围蛋白质区域的特征。或者，磷酸化可以改变蛋白质的形状，然后读者可以识别这种新的形状。我们最近发现了一个通过简单机制工作的例子：一种形状不定的波动蛋白质，当它被磷酸化时就会变成螺旋。螺旋是一种坚硬的形状，适合特定阅读器蛋白质的凹槽。值得注意的是，参与螺旋形成的蛋白质的分子和结构特征也是激酶结合和磷酸化它所必需的。对其他被磷酸化的蛋白质的分析表明，这可能会导致它们中的许多形成螺旋。我们现在的目标是阐明蛋白质的哪些特征是磷酸化所需的，以将其从动态形状转换为定义的螺旋形状。基于这一分析，我们将预测哪些其他蛋白质最有可能被交换，进行实验以测试预测，并确定它们是如何被阅读的。最后，我们将利用这些见解开发出阻止磷酸化蛋白质及其阅读器(化学抑制剂)相互作用的化学物质。这将帮助我们了解当结合被阻止时-换句话说，当信息不被传递时，癌细胞会发生什么。如果这种相互作用对癌细胞的分裂是必不可少的，那么这些化学抑制剂可以被进一步研究，以开发出新的癌症疗法。

Cells must be able to respond to changes in the human body. They grow, divide, change their shape and sometimes even die as the body requires. The millions of individual molecules that make up a cell contribute to the cell's response, and their individual actions are coordinated through an intricate cellular messaging system. One of the most common types of message is chemical modification of proteins, the presence of which may affect the location, stability or activity of that protein. The modification can also be detected by other proteins, which can then pass on the message. By analogy with written messages, the protein that carries out the modification is called a 'writer' and the protein that detects modification is called a 'reader'. Perhaps the most common modification is phosphorylation, which is written by a family of proteins called kinases, of which there are more than 500 in humans. Phosphorylation is commonly used to pass on the message that a cell is prepared to reproduce, and reaches a peak as a cell is just about to divide. Several different reader proteins are known to read the phosphorylation message. They recognize the shape and electrical charge of the phosphate group and the features of a region of the protein surrounding it. Alternatively, phosphorylation can alter the shape of the protein, and this new shape is then recognized by a reader. We recently discovered an example that works through a simple mechanism: a protein that has a fluctuating, undefined shape becomes a helix when it is phosphorylated. The helix is a rigid shape that fits into the groove of a specific reader protein. Strikingly, the molecular and structural features of the protein that are involved in helix formation are also required for the kinase to bind and phosphorylate it. Analysis of other proteins that are subject to phosphorylation suggests that this might cause many of them to form a helix. We now aim to clarify the details of what features of a protein are needed for phosphorylation to switch it from a dynamic shape to a defined helical shape. Based on this analysis, we will predict which other proteins are most likely to be switched, carry out experiments to test the predictions, and identify how they are read. Finally, we will use these insights to develop chemicals that block the interaction of the phosphorylated protein and its reader (chemical inhibitors). This will help us to understand what happens to cancer cells when the binding is blocked - in other words when the message is not passed on. If the interaction is essential for cancer cells to divide, the chemical inhibitors could be studied further for development into new cancer therapies.