The SH2 domain-containing proteins play important roles in various physiological processes and are involved in cancer development. Researchers have identified that the majority of human Src homology 2 (SH2) domains not only bind to proteins, but also interact with membrane lipids with high affinity and specificity. Their research was published in the online edition of Molecular Cell.
The SH2 domain interacts with proteins and participates in intracellular signaling by binding to phosphortyrosine (pY) residues of partner proteins. Their mode of interaction with other proteins has been well characterized for a long time.
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.
This study reveals how lipids control SH2 domain-mediated cellular protein interaction networks and suggests a new strategy for the therapeutic modulation of pY-signaling pathways. Specific inhibitors blocking the SH2 domain-lipid interaction can potentially be developed as an anti-cancer drug.
SH2 domains serve as lipid-binding modules for cell signaling
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