state. Remarkably, triggering results in a rapid decrease in the FRET signal, suggesting an “opening” of the complex (Tolar et al., 2005). It is not known what conformational change causes this decreased FRET. One interpretation is based on the model that the ITAMs may interact with the membrane prior to triggering, making the tyrosine inaccessible to kinases and preventing signaling (Aivazian and Stern, 2000). The interaction with the membrane would confine the FRET acceptor associated with the C-terminus of the ITAM bearing subunit to the membrane in proximity to the FRET donor that is kept close to the membrane by the short sIg cytoplasmic domain. Triggering would then involve dissociation of the ITAM from the membrane. A recent study using live cell FRET imaging and structure determination supports the idea that ITAM displacement from the membrane is a critical step in triggering (Xu et al., 2008). This study found that each ITAM in the TCR has a positively charged motif on its N-terminal side that interacts with acidic phospholipids in the inner leaflet and facilitates the docking of both tyrosines in the lipid bilayer where they cannot be phosphorylated. The results suggest that a change in the lipid environment to a more neutral composition is needed for ITAM access by Src family kinases (Douglass and Vale, 2005). How could a single MHC-peptide complex change the lipid environment of the TCR?
Our understanding of the basal distribution of the TCR is constrained by two seemingly contradictory results: evidence for preclustering from electron microscopy (Schamel et al., 2005) and non-correlated monomeric diffusion using fluorescence correlation spectroscopy (James et al., 2007). Long term tracking of Fce receptor movements in the context of actin bundles on rat basophilic leukemia cells shows that receptors can be corralled by actin and diffuse independently at the same time (Andrews et al., 2008). These results suggest that the clusters seen in EM maybe a result of transient confinement on monomeric recepto