Modeling GRB2 and SOS1-mediated Oligomerization of LAT: The Role of Valence Switching (89.30)

Abstract

Abstract Ligand-induced receptor aggregation is a well-known mechanism for the initiation of intracellular signals, but recent evidence also indicates that oligomerization of distal signaling molecules may be required for signal propagation. Formation of signaling complexes containing oligomers of the transmembrane adaptor protein LAT has recently been identified as a critical step in TCR-mediated signaling [Houtman et al., Nat Struct Mol Biol, 13, 798 (2006)]. Cross-linking of LAT arises from the formation of a 2:1 complex between GRB2 and SOS1, which bridges two LAT molecules through the interaction of an SH2 domain on each GRB2 with a phosphotyrosine of each LAT. We have developed a mathematical model to describe this oligomerization and determined the distribution of LAT oligomers and the kinetics of oligomer formation, which we compare with recent experimental results. The valence of LAT for binding GRB2, i.e., the number of LAT phosphotyrosines that can bind the GRB2 SH2 domain, ranges from 0 to 3 and is a critical factor in determining both the nature and extent of aggregation. A dramatic rise in oligomerization occurs between valence 2 and 3, a phenomenon we call valence switching because the valence is controlled by the extent of phosphorylation of specific LAT tyrosines. Supported by grant R37 GM35556 from the National Institutes of Health and the Department of Energy through contract DE-AC52-06NA25396.