A goal of structural biology is to make protein structure determination as routine as DNA sequencing is now. That goal is coming within reach for soluble proteins through extensive experience accumulated primarily by protein crystallographers and NMR spectroscopists. The major obstacle to progress toward that goal for human membrane proteins is the inability of currently available heterologous expression systems to routinely produce sufficient amounts of correctly folded, human membrane proteins for atomic level structure methodologies. The scarcity of atomic level structures of human membrane proteins is a problem because membrane proteins are frequent targets for drugs designed to improve human health. The hypothesis for this proposal is that eukaryotic cells producing large amounts of endogenous membrane proteins are good candidates as the foundation for novel heterologous protein expression systems producing large amounts of correctly folded human membrane proteins. This proposal will test this hypothesis with electrocytes from fish electric organ, which are exceptionally high level producers of nicotinic acetylcholine receptors.
The scarcity of atomic level knowledge about the shapes of human membrane proteins is a problem because membrane proteins are crucial to human health and to many diseases. Membrane proteins allow cells to communicate with the external world and between membrane-divided compartments within a cell. Knowing the shapes of membrane proteins is important not only for understanding how normal cells work. This understanding also helps develop disease therapies and preventions, for example, by guiding drug design. Diseases involving membrane proteins are major public health problems including neurodegenerative diseases, mental illnesses, and heart disease.
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