Text Image: UM Medical School: Graduate Program in Immunology
Text Image: Faculty

Malini Raghavan, Ph.D.
Professor of Microbiology and Immunology

malinir@umich.edu

http://www.med.umich.edu/microbio/bio/raghavan.htm


Molecular interactions in antigen presentation and host responses to virus infections

    The binding of complexes of peptides and major histocompatibility complex (MHC) class I molecules to T cell receptors is of fundamental importance for the recognition of virally infected cells by T cells. Our major interest is in the MHC class I antigen processing pathway, the cellular pathway by which complexes of peptides and MHC class I molecules are generated. 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 endoplasmic reticulum (ER) for binding to class I MHC molecules, and tapasin is an ER-resident MHC class I-specific assembly factor. Calreticulin is a generic ER chaperone, and ERp57 is a thiol-disulfide isomerase. Our goal is to understand how these proteins interact and function to orchestrate MHC class I assembly in the ER. We use molecular biology and biochemical techniques to generate desired proteins in heterologous systems. We investigate mechanisms of function using biochemical, biophysical, and cell biological approaches.

Multiple genes encode MHC class I proteins, and each gene is highly polymorphic across the population. Closely related MHC class I molecules have dramatically different intracellular trafficking rates, which could have profound functional consequences during infection. Recent genetic studies have shown that closely related MHC class I allotypes are associated with different rates of AIDS progression. Some of our current work is directed at understanding the molecular basis for these reported differences.

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Representative Publications

Li XC, Raghavan M. Structure and function of major histocompatibility complex class I antigens. Curr Opin Organ Transplant. 2010 Aug;15(4):499-504.PMID: 20613521.

Rizvi SM, Raghavan M. Mechanisms of function of tapasin, a critical major histocompatibility complex class I assembly factor. Traffic. 2010 Mar;11(3):332-47. Epub 2009 Dec 3.

Raghavan M.TAP-inhibitors from old world primate 1-herpesviruses and their use: WO2009008713. Expert Opin Ther Pat. 2010 Feb;20(2):277-82.PMID: 20100007.

Del Cid N, Jeffery E, Rizvi SM, Stamper E, Peters LR, Brown WC,
Provoda C,
Raghavan M. Modes of calreticulin recruitment to the major histocompatibility complex class I assembly pathway. J Biol Chem. 2010 Feb 12;285(7):4520-35. Epub 2009 Dec 3. PMID: 19959473.

Thammavongsa V, Schaefer M, Filzen T, Collins KL, Carrington M, Bangia N, Raghavan M. Assembly and intracellular trafficking of HLA-B*3501 and HLA-B*3503.Immunogenetics. 2009 Dec;61(11-12):703-16.PMID: 19838694.

Raghavan M, Del Cid N, Rizvi SM, Peters LR. MHC class I assembly: out and about. Trends Immunol. 2008 Sep;29(9):436-43. Review.

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.

 


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