Combinatorial diversity of Syk recruitment driven by its multivalent engagement with FcεRIγ
Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as tetrameric (αβγ2) FcεRI. Syk activation is generally attributed to binding of its tandem SH2 domains to dual phosphotyrosines within FcεRIγ-ITAMs (immunoreceptor tyrosine-based activation motifs)...
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Published in | Molecular biology of the cell Vol. 30; no. 17; pp. 2331 - 2347 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Cell Biology
01.08.2019
The American Society for Cell Biology |
Subjects | |
Online Access | Get full text |
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Summary: | Syk/Zap70 family kinases are essential for signaling via multichain immune-recognition receptors such as tetrameric (αβγ2) FcεRI. Syk activation is generally attributed to
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
-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
and
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
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
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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Center for Nonlinear Studies (CNLS) NIH National Cancer Institute (NCI) National Institutes of Health (NIH) New Mexico Spatiotemporal Modeling Center USDOE National Science Foundation (NSF) AC52-06NA25396; P50GM085273; R35GM126934; K12 GM088021; MCB170148; ACI-1548562; P30CA118100 Present addresses: †New Mexico Consortium and Pebble Labs, Los Alamos, NM 87544 Juno Pharmaceuticals, Seattle, WA 98109. |
ISSN: | 1059-1524 1939-4586 1939-4586 |
DOI: | 10.1091/mbc.E18-11-0722 |