17.4: Phosphoinositides and PIPs

Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.

Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane compartments imparts “surface identity” to the cell membrane. The phosphorylated heads of PIPs are recognized and bound by particular proteins, including proteins that help in vesicle coat assembly.

For example, the cytosolic side of the plasma membrane has high concentrations of the PI(4,5)P2, which helps recruit proteins such as dynamin and AP2 for clathrin-mediated endocytosis. PI(4,5)P2 is rapidly formed and destroyed by localized enzymes at particular locations and at specific times. This helps control the precise timing of clathrin-coated vesicle formation. Once the coated vesicle pinches off the plasma membrane during endocytosis, PI(4,5)P2 is destroyed from the site.

Many such PIs are involved in the secretory or endocytic pathways, such as PI(3)P localized at early endosomes and intraluminal vesicles of late endosomes, PI(4)P localized at the TGN, secretory granules, and synaptic vesicles; and PI(3,5)P2 localized at the late endosome boundary membrane.

Phosphatidylinositols or PI are membrane-bound lipids that are part of signaling pathways that regulate membrane traffic. They can be phosphorylated  at the carbon-3, carbon-4 and carbon 5 - positions of the inositol sugar rings to produce different phosphoinositides or PIPs.

Each organelle has its own set of enzymes to catalyze the rapid interconversion of PI and PIPs through phosphorylation and dephosphorylation. Through such modifications, these enzymes locally control the rapid binding of proteins to a membrane.

The distribution of PIPs varies between organelles as well as between regions of a continuous membrane, defining specialized membrane domains that impart a unique surface identity.

Each particular type of PIP recruits specific proteins that attach their head groups through their PIP-binding domains. The binding of proteins is locally controlled by enzymes such as PI Kinase , PIP kinase , and PIP phosphatase.

For example, PI Kinase converts Phosphatidylinositol 4-phosphate to Phosphatidylinositol 4,5-bisphosphate, which can bind Adaptor Protein AP2 on the cytosolic face of the plasma membrane. This interaction changes the conformation of the PIP, allowing the membrane to bend and expose the binding sites of embedded cargo receptors.

Once the soluble cargo molecules are loaded, the vesicles formed are ready to bud out from the plasma membrane.