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Modeling and Simulation of Aggregation of Membrane Protein LAT with Molecular Variability in the Number of Binding Sites for Cytosolic Grb2-SOS1-Grb2

Journal Article · · PLoS ONE
 [1];  [2];  [2];  [2]
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); DOE/OSTI
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
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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.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH)
Grant/Contract Number:
AC52-06NA25396; W-7405-ENG-36
OSTI ID:
1627488
Journal Information:
PLoS ONE, Journal Name: PLoS ONE Journal Issue: 3 Vol. 7; ISSN 1932-6203
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

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Cited By (5)

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Understanding the Dynamics of T-Cell Activation in Health and Disease Through the Lens of Computational Modeling journal December 2019
The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation: Adaptor protein LAT as an integration node journal November 2012
Extracellular matrix density promotes EMT by weakening cell–cell adhesions journal January 2014
The Linker for Activation of T Cells (LAT) Signaling Hub: From Signaling Complexes to Microclusters journal September 2015

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