The Erythrocyte Membrane

The erythrocyte membrane is subject a great deal of physical stress in circulation. It needs to withstand the high sheering stress in the arteries, it needs to squeeze past capillaries that ma be as small as 7.5µm and need to withstand the ionic changes. It has a well-developed network of proteins known as the erythrocyte cytoskeleton below the lipid bilayer of the plasma membrane to meet these needs. Inherited defects in these proteins have been associated with disorders of erythrocyte shape including hereditary spherocytosis, hereditary elliptocytosis, hereditary pyropoikilocytosis, Southeast Asian stomatocytosis and hereditary acanthocytosis (see table below).

Protein Gene Chromosome Disorders
α-Spectrin SPTA1 1q22-q23 Hereditary ElliptocytosisHereditary PyropoikilocytosisHereditary Spherocytosis
β-Spectrin SPTB 14q23-q24.1 Hereditary ElliptocytosisHereditary PyropoikilocytosisHereditary Spherocytosis
Ankyrin-1 ANK1 8p11.2 Hereditary Spherocytosis
Band 3 SLC4A1 17q21 Hereditary SpherocytosisHereditary AcanthocytosisSoutheast Asian OvalocytosisHereditary Stomatocytosis
Protein 4.1R EPB41 1p33-p34.2 Hereditary Spherocytosis
Protein 4.2 EPB42 15q15-q21 Hereditary Spherocytosis
Stomatin STOM 9q33.1 Hereditary Stomatocytocytosis
Glycophorin C GYPC 2q14-q21 Hereditary Elliptocytosis
Glycophorin D GYPD 2q14-q21 Hereditary Elliptocytosis

Organization of the Erythrocyte Membrane

The erythrocyte membrane consists of a lipid layer on protein scaffolding known as the cytoskeleton. The relationship between erythrocyte membrane proteins and lipid membrane bilayer is shown in the figure below. The main component of cytoskeleton is spectrin. Spectrin is tethered to the cell membrane by vertical interactions with band 3 proteins via ankyrin and protein 4.2. Spectrin also has horizontal interactions with protein 4.1R, actin, tropomodulin, tropomyosin and adducin. Protein 4.1R interacts with glycophorin C, a trans membrane protein.

Red Cell Membrane-600px

Erythrocyte Membrane Proteins


Spectrin has three functions

  1. Supporting the lipid layer
  2. Maintaining cell shape
  3. Regulating the lateral movement of integral membrane proteins.

It is made of two chains α and β that interwine to form dimers. Two dimers associate to form a tetramer which is the functional subunit. The α-chain is encoded by the gene SPTA1 at 1q22-q23 and the β-spectrin is encoded by the gene SPTB at 14q23-q24.1.


Ankyrins are ubiquitous adapter proteins thattarget diverse proteins to specialized membrane domains of smooth muscles and endoplasmic reticulum. The erythrocyte ankyrin, ankyrin-R is encoded by the gene ANK1 located at 8p11.

Band 3

Band 3 glycoprotein of the erythrocyte membrane that is coded by the gene is SLC4A1 at 17q21. The membrane domain transports anions across the cell membrane and the cytoplasmic domain provide binds the lipid membrane to spectrin via ankyrin.  major integal

Protein 4.2

Protein 4.2 regulates the interactiom of band 3 with ankyrin. It is encoded by the gene EPB42 at 1p33-p34.2.

Protein 4.1R

Protein 4.1R stabilized the spectrin-actin interactions. It is encoded by the EPB42 gene at 1p33-p34.2.

Disorders of Erythrocyte shape

Disruption in the cytoskeleton is the basis of in a viariey erythrocyte disorders charecterzid by alterations in erythrcoyte shape (see tabel and figure above). Disruption in vertical interactions results in instability of lipid layer resulting in loss of lipid layer and spherocytosis. Disruptions in horizontal interactions results in hereditary elliptocytosis.

Changes in the lipid layes also results in changes in erythrocyte shape. Unlike disorders ofthe cytskeleton, most of these disorders are accquired.

  1. Target Cells: Traget cells or codocytes are cells that have an appearance of a shooting target with a central bulls eye. Reletive increase in the membrane lipids results in the formation of target cells. This is seen in severe microcytis anaemias like severe iron deficiency, thalassaemia, haemoglobin C disease and haemoglobin E disease where the intracellular contents decrease. It may aslo bee seen in obstructive liver disease where the lipid and cholesterol content of the membrena increase.
  2. Stomatocytes: Stomatocytes are erythrocytes with a central elongated mouth-like area of pallor. Expansion of the inner layer results in stomatocytosis. This may be seen in alcoholism and with the use of vinca alkaloids.
  3. Echinocytes Ecchinocytes are cells that are no longer disc shaped and are covered by 10-30 short projections. The change is because of expansion of outer lipid layer. Ecchinocytes are seen in uraemia, pyruvate kinase deficiency or may be a fixing/staining artefact.
  4. Acanthocytes: Acanthocytes are cells with a few spiny projections on the surface (from acanthus, The Greek word for thorn). The result from accumulation of cholesterol (liver disease) or sphingomyelin (abetalipoproteinaemia) in the outer lipid layer results in acanthocytosis.

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