title: Modeling and simulation of aggregation of membrane protein LAT with molecular variability in the number of binding sites for cytosolic Grb2-SOS1-Grb2.
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.
authors.affiliation: Theoretical Biololgy and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America. ambarish.nag@nrel.gov
authors.forename: Ambarish
authors.initials: A
authors.lastname: Nag
authors.forename: Michael
authors.initials: M
authors.lastname: Monine
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
authors.forename: Byron
authors.initials: B
authors.lastname: Goldstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry*; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D001703:Biophysics / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D051380:GRB2 Adaptor Protein / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry*; D051379:Mice; D010766:Phosphorylation; D051381:Rats; D020837:SOS1 Protein / Q000737:chemistry*; D015398:Signal Transduction; D013269:Stochastic Processes; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003432:Cross-Linking Reagents; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C110810:LAT protein, human; D008565:Membrane Proteins; D020837:SOS1 Protein