Abstract
BackgroundPH domains represent one of the most common domains in the human proteome. These domains are recognized as important mediators of protein-phosphoinositide and protein-protein interactions. Phosphoinositides are lipid components of the membrane that function as signaling molecules by targeting proteins to their sites of action. Phosphoinositide based signaling pathways govern a diverse range of important cellular processes including membrane remodeling, differentiation, proliferation and survival. Myo-Inositol phosphates are soluble signaling molecules that are structurally similar to the head groups of phosphoinositides. These molecules have been proposed to function, at least in part, by regulating PH domain-phosphoinositide interactions. Given the structural similarity of inositol phosphates we were interested in examining the specificity of PH domains towards the family of myo-inositol pentakisphosphate isomers.ResultsIn work reported here we demonstrate that the C-terminal PH domain of pleckstrin possesses the specificity required to discriminate between different myo-inositol pentakisphosphate isomers. The structural basis for this specificity was determined using high-resolution crystal structures. Moreover, we show that while the PH domain of Grp1 does not possess this high degree of specificity, the PH domain of protein kinase B does.ConclusionsThese results demonstrate that some PH domains possess enough specificity to discriminate between myo-inositol pentakisphosphate isomers allowing for these molecules to differentially regulate interactions with phosphoinositides. Furthermore, this work contributes to the growing body of evidence supporting myo-inositol phosphates as regulators of important PH domain-phosphoinositide interactions. Finally, in addition to expanding our knowledge of cellular signaling, these results provide a basis for developing tools to probe biological pathways.
Highlights
PH domains represent one of the most common domains in the human proteome
Inhibition of carboxyl terminal PH domain (CPH)/PtdIns(3,4)P2 binding by inositol pentakisphosphates
A previous study suggested that the inositol pentakisphosphate, IP5(4), is a effective inhibitor of CPH binding to PtdIns(3,4)P2 [17]
Summary
PH domains represent one of the most common domains in the human proteome. These domains are recognized as important mediators of protein-phosphoinositide and protein-protein interactions. Myo-Inositol phosphates are soluble signaling molecules that are structurally similar to the head groups of phosphoinositides. These molecules have been proposed to function, at least in part, by regulating PH domain-phosphoinositide interactions. Soon after their discovery, PH domains were shown to be important for targeting host proteins to specific sites at the membrane via specific interactions with various phosphoinositides [5,6]. Phosphoinositides are lipid components of the membrane that act as key signaling molecules [7] These lipids contain an inositol head group that can be reversibly phosphorylated at the 3, 4 and 5 positions to yield seven different phosphoinositides (Figure 1, panel D)
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