Structural Studies of Ion Channel Assembly and Signaling Complexes

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DESCRIPTION (provided by applicant): The long-term goals of this project are to develop a high-resolution understanding of ion channel function and regulation. We are focused on understanding the architectural foundations that underlie the modulation and assembly of two exemplar classes of the voltage-gated ion channel (VGIC) superfamily, Kv7 and TRPM channels. Macromolecular complexes of these channels play pivotal roles in bioelectrical signaling throughout the nervous, sensory, auditory, and cardiovascular systems. Efforts are directed at understanding how intracellular modules from these channels interact with regulatory proteins and how the coiled-coil assembly domains that are a common feature of both classes direct assembly and assembly specificity determinants. We focus on two central questions: 1) What is the structural nature of the calmodulin binding apparatus in the Kv7 C-terminal tail and how do disease mutations affect calmodulin interactions with the C-terminal tail? 2) What is the structural nature of the intracellular assembly domains of TRPM and Kv7 channels and are there common themes directing heteromeric complex assembly? Elaboration of the underlying Kv7 and TRPM structural framework is essential for understanding how these and other VGICs are integrated into intracellular signaling pathways and for developing novel ways to intervene to control channel function. Our efforts encompass a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect function. Because of their important role in human physiology, VGICs are the targets for drugs with great utility for the treatment of cardiac arrhythmias, hypertension, congestive heart failure, epilepsy, and chronic pain. Thus, understanding their structures and mechanisms of action at atomic level detail should greatly assist the development of valuable therapeutic agents for a wide range of human ailments.