rs. Basal fluctuations in TCR density were observed as highly dynamic structures similar in size to microclusters, but which could not be tracked from one frame to the next (Varma et al., 2006). In order to maintain low basal activity the membrane domains in which the TCR moves prior to ligand binding will likely be highly acidic and fluid.
The lamellipodium is a relatively flat membrane region with a dense mesh of branched actin filaments translocating away from the leading edge (Svitkina et al., 1997). The mesh size of the actin gel if relatively fine, with interstitial areas on the order of 100 nm based on electron microscopy analysis of model lamellipodia (Svitkina et al., 1997). This F-actin mesh is similar in scale to the lipids domains that have been identified in membranes as lipid rafts (Sharma et al., 2004). The spatial distribution of acidic lipids like PS on the inner leaflet is not known, but structural constrains suggest that liquid ordered domains should be enriched in neutral phosphatidylethanolamine (Brown and London, 2000). I would speculate that TCR maybe confined to approximately 10% of the plasma membrane composed of disordered, fluid phase and acidic lipids, which are corralled by the mobile actin elements. In the basal state the TCR cannot be individually transported into less acidic liquid ordered domains (Fig 2). Clustering of the receptors by serial ligand binding can stabilize the interaction with the F-actin meshwork and create a sufficient force to overcome resistance to entry into less acidic domains, in which the ITAMs are exposed in the presence of Src family kinases and with depletion of CD45 together lead to triggering of the signaling cascade (Fig 2). It is likely the the “lipid rafts” also anchored to disctinct cortical actin networks and this actin may anchor these domains against movement by the dendritic actin network inivolved in the retrograde flow (Chichili and Rodgers, 2007). This model invokes shearing action of the lamellipodial actin to generate force to overcome ener