Professor of Microbiology and Immunology
Protein folding, Antigen Presentation and Immunity
Major Histocompatibility Complex (MHC) class I molecules are ligands for antigen receptors of CD8 T cells and Natural Killer cells. A major interest in our laboratory is in the MHC class I Antigen Processing and Presentation Pathway, the cellular pathway by which complexes of peptides and MHC class I molecules are generated and displayed on the cell surface. We study specific components of this pathway, including the transporter associated with antigen processing (TAP), tapasin, calreticulin, and ERp57.
TAP transports peptides from the cytosol to the ER for binding to class I MHC molecules, and tapasin is an ER-resident MHC class I-specific assembly factor. Our previous and ongoing work has helped define molecular mechanisms relevant to functions of TAP and tapasin. Human MHC class I genes are highly polymorphic, and polymorphism profoundly impacts the intracellular assembly. Recent genetic studies show that closely related MHC class I allotypes are associated with different rates of progression to AIDS, following HIV infection. Some of our current work is directed at understanding whether the intracellular assembly characteristics of an allotype influence the ability of the allotype to mediate a T or NK cell response.
Calreticulin plays important roles in the folding of MHC class I molecules and plant pattern recognition receptors. We are currently defining fundamental features of the biology of substrate interactions with calreticulin, and their regulation by co-chaperones and nucleotide. Although calreticulin is normally ER-resident, it is found at the cell surface in transformed, dying and stressed cells, where it functions as a pro-phagocytic ("eat-me") signal. Our current studies are focused on understanding roles for calreticulin in the phagocytic uptake of cancer cells and apoptotic cells, and molecular interactions relevant to calreticulin-dependent phagocytosis.
Rizvi SM, Raghavan M. Direct peptide-regulatable interactions between MHC class I molecules and tapasin. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18220-5. Epub 2006 Nov 20.
Perria CL, Rajamanickam V, Lapinski PE, Raghavan M. Catalytic site modifications of TAP1 and TAP2 and their functional consequences. J Biol Chem. 2006 Dec 29;281(52):39839-51. Epub 2006 Oct 26.
Thammavongsa V, Raghuraman G, Filzen TM, Collins KL, Raghavan M. HLA-B44 polymorphisms at position 116 of the heavy chain influence TAP complex binding via an effect on peptide occupancy. J Immunol. 177(5):3150-61, 2006
Thammavongsa V, Mancino L, Raghavan M. Polypeptide substrate recognition by calnexin requires specific conformations of the calnexin protein. J Biol Chem; 280(39):33497-505 2005.
Rizvi SM, Mancino L, Thammavongsa V, Cantley RL, Raghavan M. A polypeptide binding conformation of calreticulin is induced by heat shock, calcium depletion, or by deletion of the C-terminal acidic region. Mol Cell; 15(6):913-23, 2004.
Lapinski, P. E., Raghuraman, G., and Raghavan, M. Nucleotide interactions with membrane-bound transporter associated with antigen processing (TAP) proteins. J. Biol. Chem., 278, 8229-8237, 2003.
Raghuraman, G., Lapinski P. E and Raghavan, M. Tapasin interacts with the membrane spanning domains of both TAP subunits and enhances the structural stability of TAP1/TAP2 Complexes. J. Biol. Chem., 277, 41786-41794, 2002.
Arora, S. A. Lapinski, P. E. and Raghavan, M. The use of chimeric proteins to investigate the role of transporter associated with antigen processing structural domains in peptide binding and translocation. Proc. Natl. Acad. Sci USA, 98, 7241-7246, 2001.