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Title: Association with endoplasmic reticulum promotes proteasomal degradation of GADD34 protein
Authors: Zhou, W.
Brush, M.H.
Choy, M.S. 
Shenolikar, S.
Issue Date: 17-Jun-2011
Citation: Zhou, W., Brush, M.H., Choy, M.S., Shenolikar, S. (2011-06-17). Association with endoplasmic reticulum promotes proteasomal degradation of GADD34 protein. Journal of Biological Chemistry 286 (24) : 21687-21696. ScholarBank@NUS Repository.
Abstract: Stress-induced endogenous and ectopically expressed GADD34 proteins were present both in the cytoplasm and in membranes, with their membrane association showing similar biochemical properties. Deletion of N-terminal sequences in GADD34-GFP proteins highlighted an amphipathic helix, whose hydrophobic surface, specifically valine 25 and leucine 29, mediated endoplasmic reticulum (ER) localization. Substitution of leucines for three arginines on the polar surface indicated that the same helix also mediated the association of GADD34 with mitochondria. Fluorescence protease protection and chemical modification of cysteines substituted in the membrane-binding domain pointed to a monotopic insertion of GADD34into the outer layer of the ER membrane. Fluorescence recovery after photobleaching showed that ER association retards the mobility of GADD34 in living cells. Both WT GADD34 and the mutant, V25R, effectively scaffolded the α-isoform of protein phosphatase-1 (PP1α) and enabled eIF2α dephosphorylation. However, the largely cytosolic V25R protein displayed a reduced rate of proteasomal degradation, and unlike WT GADD34, whose ectopic expression resulted in a dilated or distended ER, V25R did not modify ER morphology. These studies suggested that the association of with ER modulates intracellular trafficking and proteasomal degradation of GADD34, and in turn, its ability to modify ER morphology. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.
Source Title: Journal of Biological Chemistry
ISSN: 00219258
DOI: 10.1074/jbc.M110.212787
Appears in Collections:Staff Publications

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