Hedgehog acyltransferase : structure and function in health and disease

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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.