Elucidating the mechanisms of accelerated dissociation and allosteric processes in the antibody immunoglobulin E

点击翻译按钮获取中文摘要

The incidence of allergic disease has increased alarmingly in recent decades, nowhere more so than in the UK, where rates are now among the highest in the world. These conditions range from mild hayfever to life-threatening severe asthma or anaphylaxis, and include allergic rhinitis, atopic dermatitis and food allergies. All of these conditions involve reactions to otherwise innocuous substances in the environment, and all involve a particular type of antibody known as IgE. We have studied this antibody over many years, and understand much about how it differs from other types of antibody such as the protective IgG antibodies. All antibodies play two important roles: they recognize and bind - usually, in the case of IgG - to foreign invaders such as bacteria or viruses using one part of the antibody molecule, and then bind via another part to "receptor" molecules on cells that become activated to destroy the foreign material. But IgE has the remarkable property of binding so tightly to the cells that once bound it almost never comes off within the lifetime of the cell. This means that when an allergen such as pollen, or peanut, or house dust mite, gets into the body (through airway, gut or skin) and binds to the IgE antibodies, they can activate the cells immediately to deliver a powerful, inflammatory response. The cells are effectively "sensitized" to react to the allergen.IgE can be targeted to alleviate allergic conditions, and an "anti-IgE" antibody therapy, called omalizumab (XolairTM), may be prescribed for certain patients with severe asthma. It works by binding to IgE molecules and blocking them from binding to the cell receptors, thus preventing sensitization; however, IgE already receptor-bound, the "pathogenic" IgE, is unaffected. It now appears that Xolair at extremely high levels, well above those reached therapeutically, can actually bind to receptor-bound IgE and actively remove it. This is a remarkable discovery, and one that would have profound implications for anti-allergy therapy if it could be understood and harnessed. We believe that the key to understanding this phenomenon lies in the unique flexibility of the IgE antibody. Our previous studies have revealed, quite unexpectedly, that the receptor-binding part of the IgE molecule can adopt several different shapes, and indeed can communicate signals from one part of the molecule to another through subtle changes in shape. This phenomenon - called allostery ("other shape") - is what we want to explore in detail using a technique that can probe these changes and this communication at the atomic level. If we can understand how binding to one part of the IgE molecule (which is accessible when IgE is bound on the cell) can release it at another site (where it binds to the receptor), then we can begin to develop a much more effective therapeutic agent for allergic disease. However, the benefits may go well beyond allergic disease. The molecular processes of health and disease ubiquitously involve interactions between different proteins, and many of these interactions, like the IgE/receptor interaction, are very tight. Targeting these protein/protein interactions is traditionally considered to be difficult, but an understanding of allostery could open up new possibilities for intervening in a range of diverse medical conditions.We are collaborating in this project with the pharmaceutical company UCB with whom we have been working for several years. They are providing protein materials for the analysis, and their interest in understanding the IgE/receptor system, publishing the results, and applying this knowledge to other protein/protein interactions will ensure the rapid dissemination and commercial translation of the results of this study.