Abstract
The linker for activation of T cells (LAT), the linker for activation of B cells (LAB), and the linker for activation of X cells (LAX) form a family of transmembrane adaptor proteins widely expressed in lymphocytes. These scaffolding proteins have multiple binding motifs that, when phosphorylated, bind the SH2 domain of the cytosolic adaptor Grb2. Thus, the valence of LAT, LAB and LAX for Grb2 is variable, depending on the strength of receptor activation that initiates phosphorylation. During signaling, the LAT population will exhibit a time-varying distribution of Grb2 valences from zero to three. In the cytosol, Grb2 forms 1∶1 and 2∶1 complexes with the guanine nucleotide exchange factor SOS1. The 2∶1 complex can bridge two LAT molecules when each Grb2, through their SH2 domains, binds to a phosphorylated site on a separate LAT. In T cells and mast cells, after receptor engagement, receptor phosphoyrlation is rapidly followed by LAT phosphorylation and aggregation. In mast cells, aggregates containing more than one hundred LAT molecules have been detected. Previously we considered a homogeneous population of trivalent LAT molecules and showed that for a range of Grb2, SOS1 and LAT concentrations, an equilibrium theory for LAT aggregation predicts the formation of a gel-like phase comprising a very large aggregate (superaggregate). We now extend this theory to investigate the effects of a distribution of Grb2 valence in the LAT population on the formation of LAT aggregates and superaggregate and use stochastic simulations to calculate the fraction of the total LAT population in the superaggregate.
Highlights
A ubiquitous method of initiating intracellular signals is through ligand-induced receptor aggregation [1,2,3]
We extend this theory to investigate the effects of a distribution of Grb2 valence in the linker for activation of T cells (LAT) population on the formation of LAT aggregates and superaggregate and use stochastic simulations to calculate the fraction of the total LAT population in the superaggregate
LAT has three terminal tyrosines, each of which when phosphorylated becomes a binding site for the adaptor protein Grb2, which through its SH2 domain, binds to phosphorylated LAT and through its two Src homology 3 (SH3) domains binds to the proline-rich regions of SOS1 [6]
Summary
A ubiquitous method of initiating intracellular signals is through ligand-induced receptor aggregation [1,2,3]. The role of aggregation in cell signaling is not restricted to bringing together the cytoplasmic domains of receptors, but occurs in multiple ways among multiple signaling molecules during the course of signaling. Scaffolding and adaptor proteins play important roles in cellular signal transduction [4,5,6,7]. The valence of a scaffolding protein for the species that induces its aggregation depends on its state of phosphorylation. The cytoplasmic domains of scaffolding proteins often have multiple binding motifs that, when phosphorylated, bind one or more types of signaling molecules. The number of phosphorylated binding motifs in a scaffolding protein molecule determines the valency of the molecule for other signaling molecules. Crosslinking of multivalent scaffolding molecules by bivalent/multivalent signaling molecules can yield branched aggregates
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