Yair Argon
Professor, Dept of Pathology and Laboratory Medicine

Cell Biology and Physiology Program

Address

816B Abramson Research Center
3615 Civic Center Boulevard
Philadelphia, PA 19104

Office tel.: 267 426-5131
Lab tel.: 267 426-5130
Fax: 267 426-5165
E-mail: yargon@mail.med.upenn.edu


Education

Hebrew University, Jerusalem: BSc (Biology), 1974.

Harvard University: PhD (Biochemistry), 1980.

Research Interests

• Functions of molecular chaperones in the immune system - modulation of antigen receptors expression and of peptide presentation.

Key words: Chaperones, BiP, GRP94, Amyloid, Light Chain, Heavy Chain, B Cell Receptor, T Cell Receptor, MHC, Peptide, Stress Response, Development.

Search PubMed for articles

Description of Research

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.

Recent Publications

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.

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.P., G. Gallo, S.M. Vogen, J.L. Dul, K.L Sciarretta, A. Kumar, R. Raffen, F.J. Stevens, and Y. Argon. 2001. Both the environment and somatic mutations govern the aggregation pathway of pathogenic immunoglobulin light chain. J. Mol. Biol., 313:1023-1036.

Vogen, S.M., T. Gidalevitz, C. Biswas, B.S. Simen, E. Stein, F. Gulmen, and Y. Argon. 2002. Radicicol-sensitive peptide binding to the N-terminal portion of GRP94. J. Biol. Chem., 277:40742-40750.

Gidalevitz, T., et al., 2004. Identification of the N-terminal peptide binding site of Glucose-regulated Protein 94. J. Biol. Chem., 279: p. 16543-16552.

Lab

Rotation Projects

1. Screening of the peptide repertoire of GRP94
2. Analysis of GRP94 deficient mice and cells
3. Chaperone-mediated tumor antigen presentation
4. Analysis of an amyloid LC-expressing transgenic mouse

Lab personnel:

Biswas, C - Research Associate
Ostrovsky, O - Postdoctoral Fellow
Makarewich, C - Technician