Combinatorial diversity of Syk recruitment driven by its multivalent engagement with FcεRIγ

Mol Biol Cell. 2019 Aug 1;30(17):2331-2347. doi: 10.1091/mbc.E18-11-0722. Epub 2019 Jun 19.


Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as tetrameric (αβγ2) FcεRI. Syk activation is generally attributed to cis binding of its tandem SH2 domains to dual phosphotyrosines within FcεRIγ-ITAMs (immunoreceptor tyrosine-based activation motifs). However, the mechanistic details of Syk docking on γ homodimers are unresolved. Here, we estimate that multivalent interactions for WT Syk improve cis-oriented binding by three orders of magnitude. We applied molecular dynamics (MD), hybrid MD/worm-like chain polymer modeling, and live cell imaging to evaluate relative binding and signaling output for all possible cis and trans Syk-FcεRIγ configurations. Syk binding is likely modulated during signaling by autophosphorylation on Y130 in interdomain A, since a Y130E phosphomimetic form of Syk is predicted to lead to reduced helicity of interdomain A and alter Syk's bias for cis binding. Experiments in reconstituted γ-KO cells, whose γ subunits are linked by disulfide bonds, as well as in cells expressing monomeric ITAM or hemITAM γ-chimeras, support model predictions that short distances between γ ITAM pairs are required for trans docking. We propose that the full range of docking configurations improves signaling efficiency by expanding the combinatorial possibilities for Syk recruitment, particularly under conditions of incomplete ITAM phosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line, Tumor
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Models, Biological
  • Models, Theoretical
  • Phosphorylation
  • Phosphotyrosine / metabolism
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, IgE / metabolism*
  • Receptors, IgE / ultrastructure
  • Signal Transduction
  • Syk Kinase / metabolism*
  • Syk Kinase / ultrastructure*
  • Tyrosine / metabolism
  • ZAP-70 Protein-Tyrosine Kinase
  • src Homology Domains


  • Intracellular Signaling Peptides and Proteins
  • Receptors, IgE
  • Phosphotyrosine
  • Tyrosine
  • Protein-Tyrosine Kinases
  • Syk Kinase
  • ZAP-70 Protein-Tyrosine Kinase
  • ZAP70 protein, human