The cell transduces information across its plasma- membrane via the engagement of surface receptors and the subsequent recruitment of intracellular proteins to these receptors or to adapter proteins to form transient and heterogeneous signaling complexes. Multi- molecular signaling complexes can, in turn, be found in large microclusters or aggregates. Such signaling complexes and clusters have been shown to play a crucial role in T cell activation and thus, in the ability of the immune system to adequately respond to foreign pathogens. However, little is known about the detailed structure, content, and organization of signaling complexes due to severe limitations of current experimental techniques. I propose to develop and apply cutting-edge super-resolution microscopy techniques, biophysical models, and statistical methods to study mechanisms of cell activation by signaling complexes in single-molecule detail in intact cells. Previously, by imaging complexes downstream of the T cell receptor at the single- molecule level with photoactivated localization microscopy (PALM), I found that these complexes show functionally significant nano-scale organization at the plasma- membrane of activated cells. I hypothesize that signaling complexes have additional levels of dynamic organization that are crucial to the plurality of functions of these complexes in adequately activating T cells. Importantly, my developed techniques and expected results will be relevant to many other signaling systems and will greatly extend our understanding of the composition, structure, and formation of signaling complexes and mechanisms of cell activation in health and disease. Such knowledge will present novel opportunities for pharmacological intervention in diseases involving inadequate immune responses and in cancer.
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