Current Research and Scholarly Interests
Our lab studies the cellular mechanisms that monitor protein biogenesis and ensure that only properly folded and assembled proteins are deployed within the cell. Proteins that fail to fold or assemble correctly can acquire alternative conformations that may give rise to highly toxic products. Therefore, cells contain machinery to recognize and destroy malfolded proteins. Mutations and genetic polymorphisms can result in the synthesis of misfolded polypeptides. Human genetic diseases therefore constitute a fertile source of naturally occurring mutants that provide insight into the nature of these “quality control” mechanisms. Both cis-acting mutations that directly affect the production of correctly assembled proteins and trans-acting mutations that affect the function of the cellular quality control machinery are linked to such diverse genetic disorders as cystic fibrosis and Lou Gehrig’s and Huntington’s diseases.
Research in the Kopito lab is focused on two general questions:
(1) How do cells make sure that only structurally “correct” proteins are deployed? How do cells discriminate between folded and misfolded
proteins? Genetic biochemical and cell biological approaches are used to identify the machinery involved in recognizing and destroying misfolded proteins.
(2) How do misfolded proteins acquire toxic properties that lead to cell death and ultimately to neurodegeneration? What mechanisms do neurons have to suppress the formation of such toxic conformers and why in some cases do these mechanisms fail? Biochemical biophysical and genetic approaches ranging from fluorescence spectroscopy to the creation of transgenic and knockout mice are applied to address these