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Professor of Pathology and Laboratory Medicine
Children's Hospital of Philadelphia email: yargon@mail.med.upenn.edu Tel: (267) 426-5131 (office) |
Orchestrating protein folding in the cell is a key process underlying the expression of membrane receptors and secreted proteins. Inefficient folding leads to inappropriate protein-protein interactions, inability to transport proteins from the ER to the Golgi complex, and is the molecular basis of many diseases. The molecular chaperones in the ER govern proper folding and assembly, recognize misfolded proteins and either improve folding or direct them to degradation. Our work focuses on two molecular chaperones, BiP and GRP94. BiP is a peptide binding protein that controls folding of many client proteins by binding selectively to some peptides in the newly synthesized proteins, in ATP-dependent fashion. Because of this ability, BiP provides an important quality control function in screening somatically mutated sequences. One project in the lab addresses how BiP recognizes normal immunoglobulin sequences and distinguishes them from aggregation-prone somatic mutants. A second project investigates the use of BiP as an inhibitor of the pathologic polymerization of proteins into amyloid fibers, both in vitro and in cell culture models. GRP94 has a different mode of action and therefore biological activity. Although it binds peptides, its prefers advanced folding intermediates. We use a combination of genetic and biochemical techniques to characterize its preferred binder peptides and map GRP94’s peptide binding site. Another project explores the use of GRP94 as a T cell vaccine, exploiting its peptide binding capacity. A third project uses our GRP94 knockout mice to define new client proteins which will explain why GRP94 is essential for determining muscle differentiation and why it has anti-apoptotic activity in many cells types. Selected Publications: Ostrovsky, O, C. Makarewich, E.L. Snapp and Y. Argon. (2009) "An essential role for ATP binding and hydrolysis in the chaperone activity of GRP94 in cells." Proc. Nat. Acad. Sci., (June 24 EPub) Ostrovsky, O, N.T. Ahmed and Y. Argon (2009) "The chaperone activity of GRP94 toward insulin-like growth factor II is necessary for the stress response to serum deprivation." Mol. Biol. Cell. 20:1855-1864. Gidalevitz, T., et al. (2004) "Identification of the N-terminal peptide binding site of glucose-regulated protein 94." J. Biol. Chem. 279:16543-16552. Dul, J.L., P. D. Davis, E.K. Williamson, F.J. Stevens, and Y. Argon. (2001) "Hsp70 and antifibrillogenic peptides promote degradation and inhibit intracellular aggregation of amyloidogenic light chains." J. Cell Biol. 152:705-715. Davis, D., R. Raffen, J.L. Dul, S. Vogen, E.K. Williamson, F.J. Stevens, and Y. Argon (2000) "Inhibition of amyloid fiber assembly by both BiP and its target peptide." Immunity 13:433-442. |
