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dc.contributor.authorMast, Steven W
dc.description.abstractIn the Endoplasmic Reticulum (ER), misfolded proteins are retro-translocated to the cytosol and degraded by the proteasome in a process known as ER-associated degradation (ERAD). !Early in this pathway, a proposed lumenal ER lectin, termed EDEM (ER degradation enhancing a-mannosidase like protein) in mammalian cells, and a homologous protein in S. cerevisiae, termed Htm1p (homologous to mannosidase protein), appear to recognize misfolded glycoproteins in the ER, disengage the nascent molecules from the folding pathway, and facilitate their targeting for degradation. !In humans there are a total of three EDEM homologs, while in S. cerevisiae two homologs may be present. The amino acid sequences of these proteins are different from other lectins, but are closely related to the Class I mannosidases (Family 47 glycosylhydrolase). In this study, gene disruption of HTM1 resulted in accumulation of the misfolded glycoprotein, mutant carboxypeptide Y (CPY*), while disruption of the second S. cerevisiae homolog had no effect on the degradation of CPY*. A study of Htm1p point mutations suggested that the catalytic site is not essential for function, while the oligosaccharide binding site of Htm1p is necessary for function. We have also characterized one of the EDEM homologs from H. sapiens, which we have termed EDEM2 (C20orf31). Using recombinantly generated EDEM2, no a-1,2 mannosidase activity was observed. In HEK293 cells, recombinant EDEM2 is localized to the ER where it can associate with misfolded a1-antitrypsin. Overexpression of EDEM2 accelerates the degradation of misfolded a1-antitrypsin indicating that the protein is involved in ER-associated degradation.
dc.subjectER-associated degradation
dc.subjectER quality control
dc.titleDiscovery of the EDEM subfamily in the family 47 glycosylhydrolases
dc.description.departmentBiochemistry and Molecular Biology
dc.description.majorBiochemistry and Molecular Biology
dc.description.advisorKelley Moremen
dc.description.committeeKelley Moremen
dc.description.committeeJeff Dean
dc.description.committeeClaiborne Glover
dc.description.committeeMichael Pierce
dc.description.committeeKojo Mensa-Wilmot

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