Flippase

FIGURE9.il Phospholipids can be flipped across a bilayer membrane by the action of flippase proteins. Wlien, by normal diffusion through the bilayer, the lipid encounters a flippase, it can be moved quickly to the other face of the bilayer. 

Flippases Proteins That Flip Lipids Across the Membrane... 

Proteins that can flip phospholipids from one side of a bilayer to the other have also been identified in several tissues (Figure 9.11). Called flippases, these proteins reduce the half-time for phospholipid movement across a membrane from 10 days or more to a few minutes or less. Some of these systems may operate passively, with no required input of energy, but passive transport alone cannot establish or maintain asymmetric transverse lipid distributions. However, rapid phospholipid movement from one monolayer to the other occurs in an ATP-dependent manner in erythrocytes. Energy-dependent lipid flippase activity may be responsible for the creation and maintenance of transverse lipid asymmetries. 

The mechanisms involved in the establishment of lipid asymmetry are not well understood. The enzymes involved in the synthesis of phospholipids are located on the cytoplasmic side of microsomal membrane vesicles. Translocases (flippases) exist that transfer certain phospholipids (eg, phosphatidylcholine) from the inner to the outer leaflet. Specific proteins that preferentially bind individual phospholipids also appear to be... 

Romsicki, Y., Sharom, F. J., Phospholipid flippase activity of the reconstituted P-glycoprotein multidrug transporter, Biochemistry 2001, 40, 6937-6947. 

Daleke, D. L. and Lyles, J. E. Identification and purification of aminophospholipid flippases. Biochim. Biophys. Acta 1486 108-112,2000. 

Analogously to the Cre-LoxP system, the 34 bp Flippase recognition target (FRT) sites are recognized by the Flippase recombination enzyme (FLP) derived from Saccharomyccs cerevisiae (28). The FLP-FRT recombination system is also utilized for the inducible genetic manipulation of the mouse genome (29, 30). 

FIGURE 11-16 Motion of single phospholipids in a bilayer, (a) Movement from one leaflet to the other is very slow, unless (b) catalyzed by a flippase in contrast, lateral diffusion within the leaflet (c) is very rapid and requires no protein catalysis. 

Flip-flop diffusion of lipids between the inner and outer leaflets of a membrane is very slow except when specifically catalyzed by flippases. 

FIGURE 11-41 Structures of two ABC transporters of E, coli, (a) The lipid A flippase MsbA (PDB ID 1JSQ) and (b) the vitamin B12 importer BtuCD (PDB ID 1L7V). Both structures are homodimers. The two nucleotidebinding domains (NBDs, in red) extend into the cytoplasm. In (b), residues involved in ATP binding and hydrolysis are shown as ball-and-stick structures. Each monomer of MsbA has six transmembrane helical segments (blue), and each monomer of BtuCD has ten. 

Amphiphilic compounds are also known as potent modifiers of the bilayer intrinsic radius of curvature and utilize this property to act as a non-specific perturbator of membrane protein function [27]. Catamphiphilic drugs that can interact with the head groups or with the scramblases or flippases can change cell functioning. 

Doerrler, W.T., Raetz, C.R.H. ATPase activity of the MsbA lipid flippase of Escherichia coli. J Biol Chem 277 (2002) 36697-36705. 

Yan, A., Guan, Z., Raetz, C.R. An undecaprenyl phosphate-aminoarabinose flippase required for polymyxin resistance in Escherichia coli. J Biol Chem 282 (2007) 36077-36089. 

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