Early analyses by SDS-PAGE of the polypeptides present in red blood cells revealed 10 major proteins (Figure 1). These proteins were initially assigned numeric designators based on their migration on SDS-PAGE. Thus, the polypeptide with the highest molecular mass, which migrates slowest, was designated band 1 protein, also known as spectrin (Table 1). As illustrated by Figure 2, certain of these proteins are glycosylated. Several span the membrane bilayer (integral membrane proteins), while others associate with its surface, generally via protein-protein interactions (peripheral membrane proteins).

Fig1. Major membrane proteins of the human red blood cell. Proteins separated by SDS-PAGE were detected by staining with Coomassie blue dye. (Reproduced with permission from Beck WS, Tepper RI: Hematology, 5th ed. Cambridge, MA: The MIT Press; 1991.)

Fig2. Interactions of cytoskeletal proteins with each other and with certain integral proteins of the membrane of the red blood cell. (Reproduced with permission from Beck WS, Tepper RI: Hematology, 5th ed. Cambridge, MA: The MIT Press; 1991.)

Table1. Principal Proteins of the Red Cell Membrane

The Red Blood Cell Membrane Contains Anion Exchange Protein & the Glycophorins

Band 3 protein is a transmembrane glycoprotein whose poly peptide chain crosses the lipid bilayer 14 times. Band 3 protein is oriented with its carboxyl-terminal end projecting from the external surface of the erythrocyte membrane and its amino terminal end from the cytosolic face. The principal function of this dimeric anion exchange protein is to provide a channel through the membrane via which chloride and bicarbonate anions generated from the hydration of CO2 can be exchanged. At the tissues, bicarbonate enters erythrocytes in exchange for chloride. At the lungs, where carbon dioxide is exhaled, this process is reversed. Band 3 protein’s amino-terminal end also serves as an anchoring point for several other red blood cell proteins, including band 4.1 and 4.2 proteins, ankyrin, hemoglobin, and several glycolytic enzymes.

Glycophorins A, B, and C are transmembrane proteins. Their membrane spanning domain consists of a single 23-amino acid arranged in the form of an α-helix. The most abundant form, glycophorin A, is comprised of a 131-amino acid polypeptide possessing 16 covalently-bound oligo saccharide chains. The majority of these are bound to the side chain hydroxyl groups of serine and threonine residues. These O-linked oligosaccharides account for roughly 60% of glycophorin A’s total mass and nearly 90% of the sialic acid residues exposed on the surface of the red cell membrane. The glycoprotein’s carboxyl-terminal end extends into the cytosol, where it binds to band 4.1 protein, which in turn is bound to spectrin. Genetic polymorphisms affecting the glycosylation of glycophorin A serve as the basis of the MN blood group system (see later). Intriguingly, individuals whose red cells lack glycophorin A exhibit no adverse effects. However, glycophorin A serves as the site of binding for several viral and bacterial pathogens, including influenza virus and the malaria parasite, Plasmodium falciparum.

Spectrin, Ankyrin, & Other Peripheral Membrane Proteins Help Determine the Shape & Flexibility of the Red Blood Cell

In order to maximize the efficiency of gas exchange, red blood cells must possess the structural strength to maintain their biconcave shape, yet remain sufficiently flexible to squeeze through peripheral capillaries and the sinusoids of the spleen. The inherently fluid and deformable foundation of the plasma membrane, the lipid bilayer, is molded to produce the erythrocyte’s characteristic biconcave shape by a strong but flexible internal network of cytoskeletal proteins (see Figure 2).

Spectrin is the most abundant protein of the erythrocyte cytoskeleton. It is composed of two polypeptides, each more than 2100 residues in length: spectrin 1 (α chain) and spec trin 2 (β chain). The α and β chains of each spectrin dimer intertwine in an antiparallel orientation to form a highly extended structural unit ≈ 100 nm in length. Normally, two spectrin dimers self-associate head-to-head to form an approximately 200-nm long heterotetramer that is linked to the inner surface of the plasma membrane (and is bridged to other spectrin tetramers) via ankyrin, actin, and band 4.1 protein. The result is an internal mesh, the cytoskeleton, that is strong enough to maintain cell shape and resist swelling due to osmotic pressure, yet flexible enough to allow the erythrocyte to fold when needed.

Band 2 protein, better known as ankyrin is a pyramid shaped protein that binds tightly to both spectrin and band 3 protein, an integral membrane protein that anchors spectrin to the membrane. Ankyrin is sensitive to proteolysis, accounting for the appearance of bands 2.2, 2.3, and 2.6, all of which are derived from intact ankyrin, which forms band 2.1.

Actin (band 5 protein) is a 42-kDa protein that can exist in two different conformations. The globular form, which is monomeric, is known as G-actin. When G-actin transitions into its filamentous, or F- form, the F-actin monomers rapidly polymerize into an extended double helical microfilament. These F-actin microfilaments bind to spectrin as well as band 4.1 protein. Band 4.1 protein is globular protein in shape and binds tightly to a site near the actin-binding domain in the tail of spectrin to form a protein 4.1-spectrin-actin ternary complex. Protein 4.1 also binds to the integral membrane proteins glycophorin A and glycophorin C, as well as certain phospholipids, thereby anchoring the ternary complex to the membrane.

Other, less quantitatively prominent proteins of the erythrocyte cytoskeleton include band 4.9 protein, adducin, and tropomyosin.

Spectrin Abnormalities Can Cause Hereditary Spherocytosis & Elliptocytosis

Hereditary spherocytosis, a genetic disease transmitted as an autosomal dominant, is characterized by hemolytic anemia and splenomegaly resulting from the presence of spherocytes (spherical red blood cells) in the peripheral blood. These spherocytes are less deformable and more prone to destruction in the spleen than normal erythrocytes, greatly shortening their life in the circulation. This condition, which affects about 1 in 5000 persons of Northern European ancestry, is caused by a deficiency in the amount or abnormalities in the structure of spectrin or, less frequently, ankyrin or band 3, 4.1, or 4.2 proteins. Loss of these proteins or impairments of their capacity to associate with other cytoskeletal components weakens the links that anchor the erythrocyte membrane to the cytoskeleton, allowing the erythrocyte to swell into a spherical shape. The anemia associated with hereditary spherocytosis is generally relieved by surgical removal of the patient’s spleen (splenectomy).

Hereditary elliptocytosis can be readily distinguished from hereditary spherocytosis by virtue of the fact that the affected red blood cells assume an elliptic shape. This condition, which affects 1 in 2500 persons of Northern European descent and is even more frequent among populations from regions where malaria is common, results from genetic abnormalities that affect spectrin or, less frequently, band 4.1 protein or glycophorin C.

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مواضيع ذات صلة

Platelets

The Biochemical Basis of The ABO System

Oxidation of Heme Iron Compromises oxygen Transport

Hypervariable Regions Confer Binding Specificity

Immunoglobulins Are Comprised of Multiple Polypeptide Chains

Serum Inhibitors Prevent Indiscriminate Proteolysis

Intracellular Iron Homeostasis is Tightly Regulated

Clinical Biochemistry of Exercise: Biochemical Adaptation

Iron is Strictly Conserved

Haptoglobin Protects the Kidneys

The Levels of Certain Plasma Proteins Increase During Inflammation or Following Tissue Damage

Albumin is the Most Abundant Protein in Human Plasma