The Walter and Eliza Hall Institute of Medical Research

Dr Matthew Call

Details

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Division: Structural Biology

Research Overview

Our joint research group has a long-standing interest in how molecular encounters outside the cell are translated into intracellular biochemical signals that direct immune responses. The now-classic example of peptide:MHC complexes binding to the T cell antigen receptor (TCR) to activate T cells has been a major focus in previous work.

While the structural determinants of MHC/TCR binding, and the construction of the TCR complex are becoming better understood, the mechanism by which receptor engagement outside the cell is sensed by signalling molecules inside the cell is still an open question. The new challenge is to understand the forces and motions linking the receptor-ligand encounter to the initiation of an intracellular biochemical signal through receptors for antigens, chemokines and other molecular cues.

We have a particular focus on how the structure and dynamics of membrane-embedded receptor domains contribute to the function of immune-signalling complexes. These portions of proteins are not mere anchors for soluble domains, but in fact provide a unique platform for protein function. They also represent the only direct physical link between ligand-binding and signalling domains across the cellular membrane.

Our lab combines biochemical and biophysical methods (both X-ray crystallography and solution NMR) with expertise in cellular and molecular immunology to study the mechanics of transmembrane signalling in the immune system. We aim to understand both how ligand binding is mechanically communicated across the lipid bilayer and how the unique physical and chemical characteristics of the membrane environment contribute to and regulate these functions.

Research Interests

Honours or PhD project available for February 2012 entry: Mechanics of transmembrane signalling in the immune system.

Selected Publications

1. Call ME, Wucherpfennig KW, Chou JJ. The structural basis for intramembrane assembly of an activating immunoreceptor complex. Nat Immunol. 2010 Oct 3. PMID: 20890284
2. Xu C, Gagnon E, Call ME, Schnell JR, Schwieters CD, Carman CV, Chou JJ, Wucherpfennig KW. Regulation of T cell receptor activation by dynamic membrane binding of the CD3epsilon cytoplasmic tyrosine-based motif. Cell. 2008 Nov 14;135(4):702-13. PMID: 19013279
3. Call ME, Wucherpfennig KW. Common themes in the assembly and architecture of activating immune receptors. Nat Rev Immunol. 2007 Nov;7(11):841-50. PMID: 17960150
4. Call ME, Schnell JR, Xu C, Lutz RA, Chou JJ, Wucherpfennig KW. The structure of the zetazeta transmembrane dimer reveals features essential for its assembly with the T cell receptor. Cell. 2006 Oct 20;127(2):355-68. PMID: 17055436
5. Feng J, Call ME, Wucherpfennig KW. The assembly of diverse immune receptors is focused on a polar membrane-embedded interaction site. PLoS Biol. 2006 May;4(5):e142. PMID: 16623599
6. Garrity D, Call ME, Feng J, Wucherpfennig KW. The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure. Proc Natl Acad Sci USA. 2005 May 24;102(21):7641-6. PMID: 15894612
7. Feng J, Garrity D, Call ME, Moffett H, Wucherpfennig KW. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity. 2005 Apr;22(4):427-38. PMID: 15845448
8. Call ME, Wucherpfennig KW. The T cell receptor: critical role of the membrane environment in receptor assembly and function. Ann Rev Immunol. 2005;23:101-25. PMID: 15771567
9. Call ME, Pyrdol J, Wucherpfennig KW. Stoichiometry of the T-cell receptor-CD3 complex and key intermediates assembled in the endoplasmic reticulum. EMBO J. 2004 Jun 16;23(12):2348-57. PMID: 15152191
10. Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell. 2002 Dec 27;111(7):967-79. PMID: 12507424

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Current Laboratory Members