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


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.

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Representative Publications

Rizvi SM, Salam N, Geng J, Qi Y, Bream JH, Duggal P, Hussain SK, Martinson J, Wolinsky SM, Carrington M, Raghavan M. Distinct assembly profiles of HLA-B molecules. J Immunol. 2014 Jun 1;192(11):4967-76. doi: 10.4049/jimmunol.1301670. Epub 2014 Apr 30. PMID: 24790147

Geng J, Sivaramakrishnan S,
Raghavan M. Analyses of conformational states of the transporter associated with antigen processing (TAP) protein in a native cellular membrane environment.J Biol Chem. 2013 Dec 27;288(52):37039-47. doi: 10.1074/jbc.M113.504696. Epub 2013 Nov 6. PMID: 2419695

Wijeyesakere SJ, Rizvi SM,
Raghavan M. Glycan-dependent and -independent interactions contribute to cellular substrate recruitment by calreticulin. J Biol Chem. 2013 Dec 6;288(49):35104-16. doi: 10.1074/jbc.M113.507921. Epub 2013 Oct 7. PMID: 24100026

Raghavan M
, Wijeyesakere SJ, Peters LR, Del Cid N. Calreticulin in the immune system: ins and outs. Trends Immunol. 2013 Jan;34(1):13-21. doi: 10.1016/j.it.2012.08.002. Epub 2012 Sep 7. Review. PMID: 22959412

Del Cid N, Shen L, Belleisle J, Raghavan M. Assessment of roles for calreticulin in the cross-presentation of soluble and bead-associated antigens.PLoS One. 2012;7(7):e41727. doi: 10.1371/journal.pone.0041727. Epub 2012 Jul 27. PMID: 22848581

Peters LR, Raghavan M.Endoplasmic reticulum calcium depletion impacts chaperone secretion, innate immunity, and phagocytic uptake of cells.
J Immunol. 2011 Jul 15;187(2):919-31. doi: 10.4049/jimmunol.1100690. Epub 2011 Jun 13. PMID: 21670312 [PubMed - indexed for MEDLINE]

Rizvi SM, Del Cid N, Lybarger L,
Raghavan M.Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules.
J Immunol. 2011 Feb 15;186(4):2309-20. doi: 10.4049/jimmunol.1002959. Epub 2011 Jan 24.

Wijeyesakere SJ, Gafni AA,
Raghavan M.Calreticulin is a thermostable protein with distinct structural responses to different divalent cation environments.
J Biol Chem. 2011 Mar 18;286(11):8771-85. doi: 10.1074/jbc.M110.169193. Epub 2010 Dec 22.

Jeffery E, Peters LR,
Raghavan M. The polypeptide binding conformation of calreticulin facilitates its cell-surface expression under conditions of endoplasmic reticulum stress.J Biol Chem. 2011 Jan 28;286(4):2402-15. doi: 10.1074/jbc.M110.180877. Epub 2010 Nov 12.

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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