Research ArticleImmunology

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

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Sci. Signal.  26 Sep 2017:
Vol. 10, Issue 498, eaal1482
DOI: 10.1126/scisignal.aal1482

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Gads’ commitment to signaling

Binding of antigen to cell surface receptors on immune cells stimulates the formation of multiprotein complexes (signalosomes) that center around adaptor proteins, such as LAT, and are mediated by the interactions of Src homology 2 (SH2) domain–containing proteins with phosphotyrosine residues in LAT. Despite having only one SH2 domain, the adaptor protein Gads preferentially binds to LAT molecules that have more than one phosphotyrosine. Through biochemical studies and mathematical modeling, Sukenik et al. showed that constitutive dimerization of Gads through its SH2 domain enabled this adaptor to discriminate between singly and multiply phosphorylated LAT proteins. Disruption of the Gads dimerization interface impaired antigen receptor signaling in T cells and mast cells. These data suggest that through dimerization, Gads commits to forming signalosomes around fully phosphorylated LAT molecules, thus promoting antigen receptor responsiveness.

Abstract

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.

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