Hedgehog acyltransferase : structure and function in health and disease

研究生物分子（如蛋白质和酶）如何在原子水平上发挥作用的能力是我们理解生命的关键-例如，单个受精卵细胞如何产生复杂的多器官生物体，如人类-并且对于更快，更有效地开发针对这些生物分子的药物也至关重要。然而，某些类型的生物分子，如存在于生物膜内的蛋白质（称为“膜蛋白”），对现代分析方法提出了重大挑战。在这里，我们提出了多种新方法来研究一种名为“刺猬酰基转移酶”（HHAT）的膜蛋白的结构和功能，该蛋白是生长和发育的关键调节因子，也与成人某些癌症的发展有关。由此产生的HHAT的分子水平的理解将授权的努力，以治疗为目标HHAT，并指导其他类似的挑战性膜蛋白的未来研究。HHAT调节“刺猬信号通路”，细胞用来相互沟通。刺猬途径是动物生长和发育的关键，并因其在果蝇中的发现而命名，其中破坏导致幼虫发育成刺猬般的尖刺外观。Hedgehog信号在健康成年人中通常被关闭，但在某些癌症中被重新激活。我们的研究将使用三种不同但互补的方法来了解HHAT的功能以及它如何影响Hedgehog信号传导。我们将使用化学生物学来创建HHAT修饰的分子的变体，这将使我们能够理解这些分子如何与HHAT相互作用。同时，我们将使用最先进的结构生物学方法，使我们能够在原子水平上可视化HHAT的三维结构。最后，我们将利用这些新的见解来了解HHAT如何在细胞中工作，并设计新的HHAT蛋白质，改变它们修饰的分子的偏好。这些新设计的HHAT将用于了解HHAT如何调节细胞之间的距离和程度，这项研究将为HHAT和Hedgehog信号在发育和疾病（如癌症）中的作用提供基本的理解，并为在设计的“合成”生物系统中调节细胞间的通信提供重要手段。它还将提供3D结构信息，并确定分子可以与HHAT结合的区域，这将大大加速药物发现工作。此外，这项工作将提供一个路线图，以指导未来针对其他相关膜蛋白的研究，这些蛋白是一系列疾病的靶点。

The ability to study how biological molecules, such as proteins and enzymes, function on an atomic level is key to our understanding of life - for example, how a single fertilised egg cell can give rise to a complex multi-organ organism like a human - and is also critical for faster and more effective development of medicines that target these biological molecules. However, certain types of biological molecules, such as proteins that exist inside biological membranes (termed 'membrane proteins'), present substantial challenges to modern methods of analysis. Here we propose to bring together multiple novel methods to study the structure and function of a membrane protein named 'Hedgehog acyltransferase' (HHAT), which is a key regulator of growth and development, and is also implicated in development of certain cancers in adults. The resulting molecular level understanding of HHAT will empower efforts to therapeutically target HHAT, and guide future studies of other similarly challenging membrane proteins.HHAT regulates the 'Hedgehog signalling pathway' that cells use to communicate with each other. The Hedgehog pathway is key to growth and development of animals, and was named after its discovery in fruit flies where disruption causes larvae to develop a spikey appearance like a hedgehog. Hedgehog signalling is generally turned off in healthy adults, but it is reactivated in certain cancers. Our research will approach the problem of understanding how HHAT functions and how this affects Hedgehog signalling using three distinct, but complimentary, approaches. We will use chemical biology to create variants of the molecules that HHAT modifies, which will allow us to understand how these molecules interact with HHAT. In parallel, we will use state-of-the-art structural biology methods to allow us to visualise the 3-dimensional architecture of HHAT at an atomic level. Finally, we will use these new insights to understand how HHAT works in cells, and to design new HHAT proteins that have altered preferences for the molecules they modify. These new designer HHAT's will be used to understand how HHAT regulates the distance and extent to which cells can communicate over.This research will provide fundamental understanding of the role of HHAT and Hedgehog signalling in development and in diseases such as cancer, and provide an important means to regulate cell-to-cell communication in designed 'synthetic' biological systems. It will also provide 3D structural information and identify regions where molecules can bind to HHAT, which will greatly accelerate drug discovery efforts. Further, this work will provide a roadmap to guide future studies against other related membrane proteins that are targets in a range of diseases.