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

Abstract

SUMMARY 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 is 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, these studies reveal how lipids control SH2 domain-mediated cellular protein-protein interaction networks and suggest a new strategy for therapeutic modulation of pY signaling pathways.

A cycle of Zap70 kinase activation and release from the TCR amplifies and disperses antigenic stimuli

“…tSH2 showed detectable association with the membrane on PLL-coated surfaces (Supplementary Fig. 1k and Supplementary Video 8), which suggested that nonspecific binding caused increased tSH2 diffusion and span trajectories 36 .…”

“…TCR-independent binding of Zap70 to the plasma membrane could take place through interactions with other membrane-associated proteins via its SH2 domains or phosphorylated tyrosine residues 46,47 . Alternatively, the carboxy-terminal SH2 domain of Zap70 contains a lipid-binding site for phosphatidylinositol trisphosphate and phosphatidylinositol-(4,5)-bisphosphate that is required for T cell activation and could facilitate direct membrane binding upon Zap70's release 36 .…”

Membrane lipids and cell signaling

“…Nonetheless, these findings have remained controversial as they lacked mechanistic details. In a recent study, Park and colleagues took on the challenge and systematically evaluated the role of lipids in regulating SH2 domain-mediated protein-protein interactions and downstream signaling events [16**]. They provided sound evidence that most SH2 domains bind with high affinity to PM lipids through their so-called “alternate cationic patches” (ACPs), which are domains adjacent to hydrophobic and/or aromatic residues reminiscent of membrane-binding protein lipid-binding sites (Figure 1b).…”

A Link Between Alzheimer's and Type II Diabetes Mellitus? Ca+2‐Mediated Signal Control and Protein Localization

“…This point is signified by recent findings in which classical PPI domains (e.g., SH2 domains) were shown to bind to negatively charged lipids as described in the following section. [16] …”

“…Previous work has demonstrated the presence of positively charged surface regions on SH2 domains that are distinct from known phosphopeptide/protein binding sites. [16] These cationic surface patches may provide an interaction surface for negatively charged lipids in membrane bilayers and, as a result, facilitate sequestration of the SH2 domain-containing protein to plasma or organelle membrane surfaces. A recent study by Park et al examined such interactions between negatively charged phosphoinositides (PIs) and 76 human SH2 domains by surface plasmon resonance (SPR).…”