Aggregation of membrane proteins by cytosolic cross-linkers: theory and simulation of the LAT-Grb2-SOS1 system.
Ligand-induced receptor aggregation is a well-known mechanism for initiating intracellular signals but oligomerization of distal signaling molecules may also be required for signal propagation. Formation of complexes containing oligomers of the transmembrane adaptor protein, linker for the activation of T cells (LAT), has been identified as critical in mast cell and T cell activation mediated by immune response receptors. Cross-linking of LAT arises from the formation of a 2:1 complex between the adaptor Grb2 and the nucleotide exchange factor SOS1, which bridges two LAT molecules through the interaction of the Grb2 SH2 domain with a phosphotyrosine on LAT. We model this oligomerization and find that the valence of LAT for Grb2, which ranges from zero to three, is critical in determining the nature and extent of aggregation. A dramatic rise in oligomerization can occur when the valence switches from two to three. For valence three, an equilibrium theory predicts the possibility of forming a gel-like phase. This prediction is confirmed by stochastic simulations, which make additional predictions about the size of the gel and the kinetics of LAT oligomerization. We discuss the model predictions in light of recent experiments on RBL-2H3 and Jurkat E6.1 cells and suggest that the gel phase has been observed in activated mast cells.
Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos, New Mexico, USA.
Ambarish
A
Nag
Michael I
MI
Monine
James R
JR
Faeder
Byron
B
Goldstein
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism*; D051380:GRB2 Adaptor Protein / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D020837:SOS1 Protein / Q000737:chemistry / Q000378:metabolism*; D013269:Stochastic Processes
D048868:Adaptor Proteins, Signal Transducing; D003432:Cross-Linking Reagents; D051380:GRB2 Adaptor Protein; C110810:LAT protein, human; D008565:Membrane Proteins; D020837:SOS1 Protein