Phosphatidylinositol structure

Ferguson, M. A. J. and Williams, A. F. (1988) Cell-surface anchoring of proteins via glycosyl-phosphatidylinositol structures. Annu. Rev. Biochem. 57 285-320. 

FIGURE 8.6 Structures of several glycerophospholipids and space-filling models of phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol. 

A bacterial phosphatidylinositol specific phospholipase C (PI-PLC) had been available for many years before it was demonstrated to strip a number of membrane-bound proteins from eukaryotic cell surfaces [1], Such proteins are anchored by a PI moiety in which the 6 position of inositol is glycosidically linked to glucosamine, which in turn is bonded to a polymannan backbone (Fig. 3-10). The polysaccharide chain is joined to the carboxyl terminal of the anchored protein via amide linkage to ethanolamine phosphate. The presence of a free NH2 group in the glucosamine residue makes the structure labile to nitrous acid. Bacterial PI-PLC hydrolyzes the bond between DAG and phosphati-dylinositols, releasing the water-soluble protein polysac charide-inositol phosphate moiety. These proteins are tethered by glycosylphosphatidylinositol (GPI) anchors. 

The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions. The exceptions are instances of synaptic transmission mediated via receptors that contain intrinsic enzymatic activity, such as tyrosine kinase or guanylyl cyclase, or via receptors that form ion channels (see Ch. 10). Heterotrimeric G proteins were first identified, named and characterized by Alfred Gilman, Martin Rodbell and others close to 20 years ago. They consist of three distinct subunits, a, (3 and y. These proteins couple the activation of diverse types of plasmalemma receptor to a variety of intracellular processes. In fact, most types of neurotransmitter and peptide hormone receptor, as well as many cytokine and chemokine receptors, fall into a superfamily of structurally related molecules, termed G-protein-coupled receptors. These receptors are named for the role of G proteins in mediating the varied biological effects of the receptors (see Ch. 10). Consequently, numerous effector proteins are influenced by these heterotrimeric G proteins ion channels adenylyl cyclase phosphodiesterase (PDE) phosphoinositide-specific phospholipase C (PI-PLC), which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and phospholipase A2 (PLA2), which catalyzes the hydrolysis of membrane phospholipids to yield arachidonic acid. In addition, these G proteins have been implicated in... 

Figure 6.6. Structure and formation of phosphatidylinositol (Ptdlns), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2). See text for details.

Lipid-protein interactions are of major importance in the structural and dynamic properties of biological membranes. Fluorescent probes can provide much information on these interactions. For example, van Paridon et al.a) used a synthetic derivative of phosphatidylinositol (PI) with a ris-parinaric acid (see formula in Figure 8.4) covalently linked on the sn-2 position for probing phospholipid vesicles and biological membranes. The emission anisotropy decays of this 2-parinaroyl-phosphatidylinositol (PPI) probe incorporated into vesicles consisting of phosphatidylcholine (PC) (with a fraction of 5 mol % of PI) and into acetylcholine receptor rich membranes from Torpedo marmorata are shown in Figure B8.3.1. 

Adhesion proteins in this group contain an immunoglobulin domain that is composed of 90-100 amino acids arranged in a sandwich of two sheets of antiparallei strands. Some members of this family also contain fibronectin type III—like domains in addition to the immunoglobulin domain. Immunoglobulin-related adhesion proteins either can exist as transmembrane structures or can be attached to cell membranes via glycosyl phosphatidylinositol links (B4, R5). 

Misra, S. and J. H. Hurley, Crystal structure of a phosphatidylinositol 3-phosphate-specific membranetargeting motif, the FYVE domain of Vps27p. Cell, 1999, 97(5), 657-66. 

Lipid transfer peptides and proteins occur in eukaryotic and prokaryotic cells. In vitro they possess the ability to transfer phospholipids between lipid membranes. Plant lipid transfer peptides are unspecific in their substrate selectivity. They bind phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and glycolipids. Some of these peptides have shown antifungal activity in vitro The sequences of lipid transfer proteins and peptides contain 91-95 amino acids, are basic, and have eight cysteine residues forming four disulfide bonds. They do not contain tryptophan residues. About 40% of the sequence adopts a helical structure with helices linked via disulfide bonds. The tertiary structure comprises four a-helices. The three-dimensional structure of a lipid transfer peptide from H. vulgare in complex with palmitate has been solved by NMR. In this structure the fatty acid is caged in a hydrophobic cavity formed by the helices. 

Figure 11.25 Structure of phosphatidylinositol bisphosphate and position of hydrolysis by phospholipase. Phosphatidylinositol 4,5-bisphosphate (PIP2) is a component of the inner leaflet of a cell membrane from which inositol 1,4,5-trisphosphate (IP3) is released by hydrolysis catalysed by phospholipase where indicated. The diacylglycerol is retained in the membrane.

The illustration shows a model of a small section of a membrane. The phospholipids are the most important group of membrane lipids. They include phosphatidylcholine (lecithin), phosphatidylethanolamine, phos-phatidylserine, phosphatidylinositol, and sphingomyelin (for their structures, see p. 50). in addition, membranes in animal cells also contain cholesterol (with the exception of inner mitochondrial membranes). Clycoli-pids (a ganglioside is shown here) are mainly found on the outside of the plasma membrane. Together with the glycoproteins, they form the exterior coating of the cell (the gly-cocalyx). 

Figure 4-4. The domain organization of an integral, transmembrane protein as well as the mechanisms for interaction of proteins with membranes. The numbers illustrate the various ways by which proteins can associate with membranes I, multiple transmembrane domains formed of a-helices 2, a pore-forming structure composed of multiple transmembrane domains 3, a transmembrane protein with a single a-helical membrane-spanning domain 4, a protein bound to the membrane by insertion into the bilayer of a covalently attached fatty acid (from the inside) or 5, a glycosyl phosphatidylinositol anchor (from the outside) 6, a protein composed only of an extracellular domain and a membrane-embedded nonpolar tail 7, a peripheral membrane protein noncova-lently bound to an integral membrane protein.

Agullo, G. et al.. Relationship between flavonoid structure and inhibition of phosphatidylinositol-3 kinase a comparison with tyrosine kinase and protein kinase C inhibition, Biochem. Pharmacol., 53, 1649, 1997. 

Helliwell, S.B. Wagner, P. Kunz, J. Deuter-Reinhard, M. Henriquez, R. Hall, M.N. TORI and TOR2 are structurally and functionally similar but not identical phosphatidylinositol kinase homologues in yeast. Mol. Biol. Cell, 5, 105-118 (1994)... 

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