Molecular Biophysical Basis of Diseases Involving Membrane Protein Dysfunction
A number of diseases involve missense mutations in genes encoding membrane proteins that result in protein dysfunction and/or misfolding and mistrafficking early in the secretory pathway. The Sanders lab seeks to elucidate the molecular biophysical mechanisms by which such mutations result in these defects. We are pursuing several systems, including Long QT Syndrome mutant forms of both the human potassium KCNQ1 channel and a modulatory partner, KCNE1. Mutations in either of these proteins result in altered channel functional properties that throw off the timing and electrical properties of the cardiac action potential in a way that can result in serious, even fatal arrhythmias. Our approach is to carry out studies of purified membrane proteins using solution NMR spectroscopy and then correlate observations from these studies with what is known about the behavior of the corresponding mutant protein in vivo.