Dimerization of the adaptor Gads facilitates antigen receptor signaling by promoting the cooperative binding of Gads to the adaptor LAT

Sci Signal. 2017 Sep 26;10(498):eaal1482. doi: 10.1126/scisignal.aal1482.


The accurate assembly of signalosomes centered on the adaptor protein LAT (linker of activated T cells) is required for antigen receptor signaling in T cells and mast cells. During signalosome assembly, members of the growth factor receptor-bound protein 2 (Grb2) family of cytosolic adaptor proteins bind cooperatively to LAT through interactions with its phosphorylated tyrosine (pTyr) residues. We demonstrated the Src homology 2 (SH2) domain-mediated dimerization of the Grb2 family member, Grb2-related adaptor downstream of Shc (Gads). Gads dimerization was mediated by an SH2 domain interface, which is distinct from the pTyr binding pocket and which promoted cooperative, preferential binding of paired Gads to LAT. This SH2 domain-intrinsic mechanism of cooperativity, which we quantified by mathematical modeling, enabled Gads to discriminate between dually and singly phosphorylated LAT molecules. Mutational inactivation of the dimerization interface reduced cooperativity and abrogated Gads signaling in T cells and mast cells. The dimerization-dependent, cooperative binding of Gads to LAT may increase antigen receptor sensitivity by reducing signalosome formation at incompletely phosphorylated LAT molecules, thereby prioritizing the formation of complete signalosomes.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • GRB2 Adaptor Protein / genetics
  • GRB2 Adaptor Protein / metabolism*
  • Humans
  • Jurkat Cells
  • Mast Cells / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Models, Biological
  • Multiprotein Complexes / metabolism
  • Mutation
  • Phosphorylation
  • Primary Cell Culture
  • Protein Multimerization*
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / metabolism*
  • Tyrosine / metabolism
  • src Homology Domains / physiology


  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • LAT protein, human
  • Membrane Proteins
  • Multiprotein Complexes
  • Receptors, Antigen, T-Cell
  • Tyrosine