Mechanics of transmembrane signalling in the immune system

Project type

Honours and/or PhD

Supervisor(s) Division Email

Dr Matthew Call

(Primary)		 Structural Biology .(JavaScript must be enabled to view this email address)

Dr Melissa Call

 

(Co-supervisor)		 Structural Biology .(JavaScript must be enabled to view this email address)

 

Details of project

The Call laboratory has several potential projects on offer that are related to the structural characterisation of immune receptor complexes. We have been studying a class of receptors that are made up of multiple membrane protein subunits that act as either ligand-binding modules or signal-transducing modules (see figure below). These receptors are responsible for activating lymphocytes such as T cells and natural killer (NK) cells in response to infection, and understanding the structures of the intact, membrane-embedded complexes is a crucial step in describing the mechanisms of receptor activation.

In previous work, we and others have identified the transmembrane (TM) domains of receptor subunits as important points of physical contact that direct the assembly of immune receptor complexes (see project references 1-3). These segments of proteins are very difficult to study and have historically constituted a significant 'blind spot' in structural analyses of all kinds of TM receptors. We have pioneered a set of techniques for solving the structures of membrane-embedded peptide complexes (see figure; project references 4 and 5) and we are now applying them to study the structure and dynamics of several types of important lymphocyte receptors.

A student taking on one of these projects will be involved in designing and producing TM peptide complexes, collecting and analysing solution NMR data, calculating new structures and performing biochemical analyses to test structure-based predictions about receptor function. The results of these studies will provide fundamental new insights into the earliest stages of immune activation.

Project references

  1. 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
  2. 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
  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. Call ME, Wucherpfennig KW, Chou JJ. The structural basis for intramembrane assembly of an activating immunoreceptor complex. Nat Immunol. 2010 Oct 3. PMID: 20890284

 

Research interests

Research in the Call laboratory is broadly focussed on understanding how cellular signalling and molecular recognition events take place in the context of the plasma membrane. Cells of the immune system must exchange a vast amount of information with each other and with their surroundings in order to direct appropriate responses to potential pathogens, cancerous cells and injured tissues. This information exchange is achieved primarily through the actions of a broad array of cell-surface receptors expressed on lymphocytes and other immune cells that integrate many different types of signals to regulate immune functions.

Decades of research into immune signalling pathways have produced a large base of knowledge about the molecules involved, but in most cases we still do not understand the mechanics of information transmission across the lipid bilayer. Our laboratory has taken a particular interest in how the structure and dynamics of the membrane-embedded portions of receptors and their associated proteins contribute to immune regulation. These transmembrane domains turn out to be much more than mere anchors to the lipid bilayer – they organise complex membrane protein interactions and participate in dynamic regulatory processes. They also represent the only direct physical link between ligand-binding and signalling domains across the cell membrane, and we therefore have a keen interest in obtaining the detailed structural information required to accurately describe their roles in signalling.

Our lab combines expertise in protein engineering, biophysical methods (primarily solution NMR) and molecular immunology to unravel the mechanics of transmembrane signalling in the immune system. Our aim is to understand both how ligand binding to a receptor is physically communicated through the lipid bilayer and how the unique characteristics of the membrane environment contribute to and regulate this communication.

Selected publications

  1. Call ME, Chou JJ. A view into the blind spot: solution NMR provides new insights into signal transduction across the lipid bilayer. Structure. 2010 Dec 8;18(12):1559-1569. PMID: 21134635
  2. Wucherpfennig KW, Gagnon E, Call MJ, Huseby ES, Call ME. Structural biology of the T-cell receptor: insights into receptor assembly, ligand recognition, and initiation of signaling. Cold Spring Harb Perspect Biol. 2010 Apr 1;2(4):a005140 PMID: 20452950
  3. 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

Research theme

Infectious diseases

Scientific discipline

  • Biochemistry
  • Immunology
  • Structural Biology

Keywords

Immune receptor, signalling, lymphocyte activation, membrane protein, structure, NMR

Sponsors

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