Protein quality control mechanisms are required for normal cellular health to prevent disease and avoid premature senescence. Unique mutant proteins are substrates of these pathways, are recognized by protein quality control pathway components and typically degraded by the proteasome. Proteins with subtle missense mutations can retain function yet degradation by these pathways can underlie pathogenesis. The molecular and physical basis of protein quality control substrate recognition are poorly understood, especially for soluble cytosolic proteins. This application proposes to use a powerful multi disciplinary approach to define novel proteins in the protein quality control pathway and elucidate the physical and structural basis of substrate recognition.
Protein quality control mechanisms are required for normal cellular health to prevent disease and avoid premature senescence. Heritable missense mutations produce large quantities of mutant proteins that are recognized as mutant and degraded by various mechanisms. Unique mutant protein substrates bearing subtle mutations but remaining functional are degraded by these pathways yet the physical basis of their recognition and detection are poorly understood, especially for soluble cytosolic proteins. This application proposes to use a powerful multi disciplinary approach to define novel proteins in the protein QC pathway and elucidate the basis of substrate recognition.
|Drombosky, Kenneth W; Rode, Sascha; Kodali, Ravi et al. (2018) Mutational analysis implicates the amyloid fibril as the toxic entity in Huntington's disease. Neurobiol Dis 120:126-138|
|Roland, Bartholomew P; Zeccola, Alison M; Larsen, Samantha B et al. (2016) Structural and Genetic Studies Demonstrate Neurologic Dysfunction in Triosephosphate Isomerase Deficiency Is Associated with Impaired Synaptic Vesicle Dynamics. PLoS Genet 12:e1005941|
|Dong, Wei; Zhang, Xuejing; Liu, Weijie et al. (2015) A conserved polybasic domain mediates plasma membrane targeting of Lgl and its regulation by hypoxia. J Cell Biol 211:273-86|
|Roland, Bartholomew P; Amrich, Christopher G; Kammerer, Charles J et al. (2015) Triosephosphate isomerase I170V alters catalytic site, enhances stability and induces pathology in a Drosophila model of TPI deficiency. Biochim Biophys Acta 1852:61-9|
|Towheed, Atif; Markantone, Desiree M; Crain, Aaron T et al. (2014) Small mitochondrial-targeted RNAs modulate endogenous mitochondrial protein expression in vivo. Neurobiol Dis 69:15-22|
|Hrizo, Stacy L; Fisher, Isaac J; Long, Daniel R et al. (2013) Early mitochondrial dysfunction leads to altered redox chemistry underlying pathogenesis of TPI deficiency. Neurobiol Dis 54:289-96|
|Roland, Bartholomew P; Stuchul, Kimberly A; Larsen, Samantha B et al. (2013) Evidence of a triosephosphate isomerase non-catalytic function crucial to behavior and longevity. J Cell Sci 126:3151-8|