Structural biology of cell surface receptors
The identification tag of the Dscam receptor is encoded in a palindromic hydrogen bonding network. Two receptors that contain the same code bind together, but a slight difference in amino acid sequence prevents binding. The Drosophila Dscam gene is spliced to generate 19 008 different receptors that provide each neuron in the brain with a unique identity tag. This helps the neurons to orient themselves, and to decide where to form a connection with another neuron.
The Meijers group studies how clusters of molecules on a cell's surface rearrange themselves when they encounter another cell.
Previous and current research
Intercellular interactions occur through supramolecular clusters that form asymmetric kinapses when a cell is scanning the environment, and symmetric synapses when cell-cell recognition is established. This ancient recognition process has been observed in as diverse systems as predatory amoeba, lymphocytes scanning for antigens, and nerve cells seeking connections to form a brain map. At the centre of these interactions are very specific molecular recognition events that trigger a reorganisation of the cluster on the cell surface, amplifying the recognition event, resulting in the activation of a signalling cascade within the cell that leads to physiological changes.
Immune receptors: T cell receptors (TCR) on lymphocytes are the central recognition unit of a supramolecular complex that scans for pathogenic peptides loaded on MHC molecules at the surface of host cells. We have studied the molecular basis for the dominant response of the adaptive immune system to certain influenza peptides, which provides insights that should help in the design of a peptide vaccine against influenza (Meijers et al., 2005). We have also studied the interaction between the T cell receptor/MHC complex and CD4, a cell surface receptor that acts as a co-receptor in T cell recognition (Wang et al., 2001). CD4 is a prime fusion target of the HIV virus, and the structure between CD4 and the MHC class II molecule I-Ak shows that the viral envelope protein gp120 and the MHC molecule bind the same region of CD4. The structure confirmed that immunodeficiency is caused in part by the disruption of the binding of MHC class II molecules to CD4, an essential coreceptor in the supramolecular TCR complex.
Neuronal receptors: The nervous system consists of neuronal circuits, and it is thought that the individual neurons find their targets and establish synaptic connections within the circuit following a specific developmental program. Some of the molecules that guide the neurons to their targets are cell surface receptors that provide a unique identity tag to each neuron. The Down syndrome cell adhesion molecule (Dscam) from Drosophila was identified as an axon guidance receptor that has the potential to provide a large number of unique identity tags. Dscam contains three variable extracellular immunoglobulin domains, which can provide 19 008 unique cell surface receptor identity tags through splicing. We have studied the structural basis for the remarkable specificity of the receptor, which seems to interact only with receptors that consist of identical isoforms (Meijers et al., 2007). The structure shows how variable regions of the Dscam receptor interact through a palindromic hydrogen bonding network that is unique for each isoform.
Future Projects and Goals
Viruses and bacterial pathogens use cell surface receptors to invade host cells, but they also deregulate the order established in the supramolecular cluster to jam the recognition machinery of the host. The same (de)regulation mechanism is used by the immune system itself, which employs internal regulators that act on the synapse (such as hormones and cytokines) to tune the response of the immune system. We are using molecular fragments of pathogenic and self-regulating factors to gauge the interactions with and within the supramolecular complex. A detailed understanding of these interactions will allow us to tinker with cell surface receptors in order to manipulate the behaviour of certain individual cells.