SH2 Domains Serve as Lipid-Binding Modules for pTyr-Signaling Proteins

The Src-homology 2 (SH2) domain is a protein interaction domain that directs myriad phosphotyrosine (pY)-signaling pathways. Genome-wide screening of human SH2 domains reveals that ∼90% of SH2 domains bind plasma membrane lipids and many have high phosphoinositide specificity. They bind lipids using surface cationic patches separate from pY-binding pockets, thus binding lipids and the pY motif independently. The patches form grooves for specific lipid headgroup recognition or flat surfaces for non-specific membrane binding and both types of interaction are important for cellular function and regulation of SH2 domain-containing proteins. Cellular studies with ZAP70 showed that multiple lipids bind its C-terminal SH2 domain in a spatiotemporally specific manner and thereby exert exquisite spatiotemporal control over its protein binding and signaling activities in T cells. Collectively, this study reveals how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY-signaling pathways. [Display omitted] •SH2 domains bind lipids with high affinity and specificity•Lipids coordinate SH2 domain-mediated protein-protein interactions•Lipids spatiotemporally control ZAP70-signaling activities in T cells•Lipid-binding sites of SH2 domains represent a pharmacological target SH2 domains mediate complex protein-protein interactions during diverse cell-signaling pathways. Park et al. discover that lipids directly bind SH2 domains and modulate SH2 domain-mediated protein-protein interactions. PI45P2 and PIP3 spatiotemporally coordinate T cell-signaling activities through their interaction with SH2 domains of signaling proteins, including ZAP70.