Research Specialty: Structural and chemical biology of membrane proteins. Membrane protein misfolding and disease. Alzheimer’s disease, Charcot-Marie-Tooth Disease, cardiac arrhythmias, kidney fibrosis Research Description: Molecular Biophysical Basis of Diseases Related to Membrane Protein Dysfunction and Misfolding A surprising number of diseases are caused or impacted by missense mutations in genes encoding membrane proteins that result in protein dysfunction and/or misfolding and mistrafficking early in the secretory pathway. We seek to elucidate the molecular biophysical mechanisms by which such mutations result in these defects. Our approach is to carry out studies of purified membrane proteins under well-controlled conditions and then correlating observations from these studies with what is known about the behavior of the corresponding mutant protein in vivo. We are pursuing several systems. We have discovered that the amyloid precursor protein (APP) that is closely associated with the development of Alzheimer’s disease binds cholesterol in a way that may help to control production of the amyloid-beta polypeptide. We seek to understand exactly how and why cholesterol binds to APP and by what mechanisms this regulates amyloid-beta production. A second system involves Long QT Syndrome mutant forms of both the human KCNQ1 potassium channel and a modulatory partner, KCNE1. We are unraveling the mechanisms by which mutations in either of these proteins result in serious, even fatal cardiac arrhythmias. Another project involves a protein of the human peripheral nervous system known as peripheral myelin protein 22 (PMP22). PMP22 is known to undergo mutation-prompted misfolding which results in Charcot-Marie-Tooth Disease.