The red cell membrane

Sphingomyelin Phosphatidylcholine

Figure 8.2 Main lipids of the red cell membrane. The outer, plasma layer, contains most of the neutral lipids sphingomyelin and phosphatidylcholine (lecithin). The inner, cytoplasmic layer, contains mostly acidic groups, phosphatidylserine, ethanolamine and inositol. 'R' may be choline, serine, ethanolamine or inositol.

Figure 8.2 Main lipids of the red cell membrane. The outer, plasma layer, contains most of the neutral lipids sphingomyelin and phosphatidylcholine (lecithin). The inner, cytoplasmic layer, contains mostly acidic groups, phosphatidylserine, ethanolamine and inositol. 'R' may be choline, serine, ethanolamine or inositol.

The red cell membrane, like all other cell membranes, consists of a lipid bilayer that is stabilized and given specific properties by the proteins, glycolipids and other specialized molecules and structures with which it is associated.

The lipid bilayer consists of approximately equal molar quantities of phospholipids and cholesterol molecules. The charged phosphatidyl groups of the phospholipids are hydrophilic and form the outer and inner surfaces of the bilayer. The interior of the membrane is formed by hydrophobic bonding of the acyl chains and cholesterol, which form the internal parts of the two leaflets (Figure 8.1). The arrangement is energy efficient but the two leaflets are not symmetrical. The outer leaflet consists mainly of phosphatidylcholine and sphingomyelin, inner leaflet phosphatidylethanolamine and phosphatidylserine (Figure 8.2). The maintenance of the asymmetry and the proper function of the membrane requires energy. In the mature red cells; this is provided by ATP from the glycolytic pathway and reducing power mainly in the form of glutathione.

The normal biconcave shape and function of the red cell membrane are determined by the membrane proteins and their interactions with the lipid bilayer and with each other. There are two main sorts of protein-membrane associations. The integral proteins have strong hydrophobic domains that associate with the hydrophobic part of the bilayer. Many of these integral proteins span the membrane and provide channels between the plasma and cytosolic compartments. The cytostolic, inner domains of these proteins interact with each other and with the second main group, the proteins of the cytoskeleton. The integral proteins that provide the links between the plasma surface and the cytoskeleton have conveniently been referred to as 'vertical con nections', whereas the proteins of the cytoskeleton that make up the inner network of the cell membrane are characterized as 'horizontal connections'. Genetic abnormalities that produce spherocytes mainly have mutations affecting the vertical connections. Mutations of the horizontal system usually produce elliptocytosis or more bizarre-shaped changes. The main proteins are listed in Table 8.2, and their arrangement is shown schematically in Figure 8.3.

In addition to the compartments mentioned so far, there are numerous surface proteins that provide the main interface with the plasma, including the blood group systems and other

Table 8.2 Proteins of the red cell membrane.

Band*

Protein

Gene location Function

Associated

haemolytic anaemias

1

a-Spectrin

SPTA1,1q21 Cytoskeleton network

HE, HS

2

ß-Spectrin

SPTB, 14q22-q23 Cytoskeleton network

HPP

2.1

Ankyrin

ANK1, 8p11.2 Vertical contact

HS

2.9

Adducin ADD1, ADD2

a chain 10q24.2-q24.3, P-chain Promotes spectrin binding to actin,

(HS, HE in mice)

4p16.3 binds Ca+/calmodulin

3

Band 3. Solute carrier

EPB3 (SLC4A1), 17q21-q22 Anion exchange channel, ii blood

HS, SAO, HAC

family 4 (anion exchanger)

groups, binds glycolytic enzymes

member 1

4.1

Protein 4.1

EPB41, 1p36.2-p34 Stabilizes spectrin-actin contact

HE

4.2

Protein 4.2 (pallidin)

EPB42(PLDN), 15q15 Spectrin-ankyrin complex

HS (Japan)

5

ß-Actin

ACTB, 7p22-p12 Spectrin network junction

?

6

Ga3PD

12p13.31-p13.1 Links ATP production to membrane

?

PAS+-1

Glycophorin A

4q28.2-q31.1 MN blood groups

?

PAS-2

Glycophorin C

2q14-q21 Gerbich blood groups

HE

PAS-3

Glycophorin B

4q28-q31 Ss blood groups

?

HAC, hereditary acanthocytosis; HE, hereditary elliptocytosis; HS, hereditary spherocytosis; HPP, hereditary pyropoikilocytosis; SAO, South-East Asia ovalocytosis; Ga3PD, gyceraldehyde-3-phosphate dehydrogenase. *The band numbers refer to the position on SDS-PAGE electrophoresis. Periodic acid-Schiff stain - bands seen only on PAS-stained gels.

Mns Glycophorin

Horizontal interaction

Tropomodulin

Horizontal interaction

Tropomodulin

Figure 8.3 Arrangement of membrane proteins (after Tse & Lux, 1999, with permission).

receptors. Many of these molecules are heavily glycosylated, as are the integral proteins the glycophorins. Sialic acid, which is the main side-chain of the glycophorins, contributes the most part to the negative surface change of the erythrocyte. Many of these surface proteins are linked to the membrane by the glycosyl phosphatidylinositol (GPI) anchor, which provides the hydrophobic domain required for association with the inner hydrophobic part of the membrane. Somatic mutations in the gene phosphatidylinositol glycan A (PIG-A) leads to a failure to produce the anchor and to paroxysmal nocturnal haemoglo-binuria (PNH), as discussed in Chapter 11.

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