n-receptor tyrosine kinases to 10 docking sites, the immunotyrosine based activation motifs (ITAMs), in response to ligand binding. With all these docking sites, it is not clear that dimerizing this receptor would increase its activity. Recent studies have provided indirect evidence that monovalent ligands can trigger TCR microclusters and signaling events without directly cross-linking the receptor to form dimers e.g.(Varma et al., 2006). It is interesting at this point to think about how the TCR would sense such a monovalent engagement event? Recent data from the BCR and TCR systems provide insights into accessibility changes in cytoplasmic domains of the receptor during triggering and provide raw material for a draft model that incorporates an early role for F-actin.
The BCR has two signal transduction subunits with one ITAM in each. BCR with a FRET donor at the C-terminus of transmembrane immunoglobulin (sIg) and a FRET acceptor on the C-terminus of Igα have a high FRET signal in the basal, non-signaling 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 intera