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.
Endoplasmic reticulum calcium depletion impacts chaperone secretion, innate immunity, and phagocytic uptake of cells.
Peters LR, Raghavan M. J Immunol. 2011 Jul 15;187(2):919-31. Epub 2011 Jun 13.
Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules.
Rizvi SM, Del Cid N, Lybarger L, Raghavan M. J Immunol. 2011 Feb 15;186(4):2309-20. Epub 2011 Jan 24.
Calreticulin is a thermostable protein with distinct structural responses to different divalent cation environments.
Wijeyesakere SJ, Gafni AA, Raghavan M. J Biol Chem. 2011 Mar 18;286(11):8771-85. Epub 2010 Dec 22.
The polypeptide binding conformation of calreticulin facilitates its cell-surface expression under conditions of endoplasmic reticulum stress.
Jeffery E, Peters LR, Raghavan M. J Biol Chem. 2011 Jan 28;286(4):2402-15. Epub 2010 Nov 12.
Structure and function of major histocompatibility complex class I antigens.
Li XC, Raghavan M. Curr Opin Organ Transplant. 2010 Aug;15(4):499-504. Review.
TAP-inhibitors from old world primate 1-herpesviruses and their use: WO2009008713.
Raghavan M. Expert Opin Ther Pat. 2010 Feb;20(2):277-82.
Mechanisms of function of tapasin, a critical major histocompatibility complex class I assembly factor.
Rizvi SM, Raghavan M. Traffic. 2010 Mar;11(3):332-47. Epub 2009 Dec 3.
Modes of calreticulin recruitment to the major histocompatibility complex class I assembly pathway.
Del Cid N, Jeffery E, Rizvi SM, Stamper E, Peters LR, Brown WC, Provoda C, Raghavan M. J Biol Chem. 2010 Feb 12;285(7):4520-35. Epub 2009 Dec 3.
Assembly and intracellular trafficking of HLA-B*3501 and HLA-B*3503.
Thammavongsa V, Schaefer M, Filzen T, Collins KL, Carrington M, Bangia N, Raghavan M. Immunogenetics. 2009 Dec;61(11-12):703-16.
MHC class I assembly: out and about.
Raghavan M, Del Cid N, Rizvi SM, Peters LR. Trends Immunol. 2008 Sep;29(9):436-43. Review.
Direct peptide-regulatable interactions between MHC class I molecules and tapasin.
Rizvi SM, Raghavan M. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18220-5. Epub 2006 Nov 20.
Catalytic site modifications of TAP1 and TAP2 and their functional consequences.
Perria CL, Rajamanickam V, Lapinski PE, Raghavan M. J Biol Chem. 2006 Dec 29;281(52):39839-51. Epub 2006 Oct 26.
HLA-B44 polymorphisms at position 116 of the heavy chain influence TAP complex binding via an effect on peptide occupancy.
Thammavongsa V, Raghuraman G, Filzen TM, Collins KL, Raghavan M. J Immunol. 2006 Sep 1;177(5):3150-61.
Identification of domain boundaries within the N-termini of TAP1 and TAP2 and their importance in tapasin binding and tapasin-mediated increase in peptide loading of MHC class I.
Procko E, Raghuraman G, Wiley DC, Raghavan M, Gaudet R. Immunol Cell Biol. 2005 Oct;83(5):475-82.
Polypeptide substrate recognition by calnexin requires specific conformations of the calnexin protein.
Thammavongsa V, Mancino L, Raghavan M. J Biol Chem. 2005 Sep 30;280(39):33497-505. Epub 2005 Aug 1.
A rare transporter associated with antigen processing polymorphism overpresented in HLAlow colon cancer reveals the functional significance of the signature domain in antigen processing.
Yang T, Lapinski PE, Zhao H, Zhou Q, Zhang H, Raghavan M, Liu Y, Zheng P. Clin Cancer Res. 2005 May 15;11(10):3614-23.
A polypeptide binding conformation of calreticulin is induced by heat shock, calcium depletion, or by deletion of the C-terminal acidic region.
Rizvi SM, Mancino L, Thammavongsa V, Cantley RL, Raghavan M. Mol Cell. 2004 Sep 24;15(6):913-23.
Nucleotide interactions with membrane-bound transporter associated with antigen processing proteins.
Lapinski PE, Raghuraman G, Raghavan M. J Biol Chem. 2003 Mar 7;278(10):8229-37. Epub 2002 Dec 25.
Responses of herpes simplex virus type 1-infected cells to the presence of extracellular antibodies: gE-dependent glycoprotein capping and enhancement in cell-to-cell spread.
Rizvi SM, Raghavan M. J Virol. 2003 Jan;77(1):701-8.
Tapasin interacts with the membrane-spanning domains of both TAP subunits and enhances the structural stability of TAP1 x TAP2 Complexes.
Raghuraman G, Lapinski PE, Raghavan M. J Biol Chem. 2002 Nov 1;277(44):41786-94. Epub 2002 Sep 3.