The Hb tetramer consists of two pairs of unlike globin polypeptide chains, each associated with a heme group. Normal Hb has two α-globin and two non-α-globin chains; the interaction of these chains is responsible for the quaternary structure of the Hb molecule and normal oxygen transport. Functionally, the second exon of each globin gene encodes the major component of the heme binding pocket, and the α and non-α contacts are regulated by the third exon.

The behavior of Hb is determined by its primary structure, the covalent linking of amino acids to form the polypeptide globin. The higher-order structures of Hb depend on the sequence of amino acid residues that make up the globin chain. The α-globin chains contain 141 residues, and the β-globin–like chains are 146 amino acids long (Fig. 1). There is considerable homology among these globins, especially among the non-α-globin chains. Whereas the α-globin genes (HBA2, HBA1) result from a very ancient gene duplication, the non-α-globin genes (HBE, HBG2, HBG1, HBD, HBB) are the result of more recent gene duplications and are more akin to each other than they are to the α-like globin genes. Gene conversion events also ensure the similarity of duplicated genes.

Fig1. THE Β-GLOBIN CHAIN SHOWING HELICAL AND NONHELICAL SEGMENTS. The helical segments are labeled A through H, and the nonhelical segments are designated NA for residues between the N terminus and the A helix, CD for residues between the C and D helices, and so forth. (Reproduced with permission from Huisman THJ, Schroeder WA. New Aspects of the Structure, Function, and Synthesis of Hemoglobin. Boca Raton, FL: CRC Press; 1971.)

Elements of the secondary structure of globin are shown in Figs. 1 and 2. Approximately 75% of the globin polypeptide chain forms an α-helix. There are eight helical segments, A through H, separated by short stretches from which the α-helix is absent. These nonhelical segments permit folding of the polypeptide on itself and are often dictated by the presence of prolyl residues, which are generally unable to participate in the formation of α-helices. Although the helical segments of the α-globin and non-α-globin chains do not exactly correspond, it is possible to align amino acid residues in all globin peptides by their helical and nonhelical residue numbers, as indicated in Fig. 3. This permits greater appreciation of the homology among globins. Some of the amino acids of globin are invariant, or conserved, in the sense that they are preserved during phylogeny. These residues occur at portions of the molecule that are critical for its stability and function, such as heme-binding residues, hydrophobic amino acids of the interior of the molecule, and certain subunit contacts at the α1–β2 interface. The introduction of prolyl residues into α-helical segments by mutation leads to interruption of the α-helix and instability of the resulting Hb molecule.

Fig2. TERTIARY STRUCTURE OF A GLOBIN CHAIN. Globin folds into a tertiary structure such that polar or charged amino acids are located on the exterior of the molecule and the heme ring resides in a hydro phobic niche between the E and F helices. Linked to the heme are the proxi mal (F8) histidine and the distal (E7) histidine. (Reproduced with permission from Perutz MF. Molecular anatomy, physiology, and pathology of hemoglobin. In: Stamatoyannopoulos G, Neinhuis AW, Leder P, et al., eds. The Molecular Basis of Blood Diseases. Philadelphia, PA: Saunders; 1987:127.)

Fig3. OXYGEN DISSOCIATION CURVE OF HEMOGLOBIN. The percent saturation of hemoglobin (Hb) with oxygen at different oxygen tensions is depicted by the red sigmoidal curve. The P50 (i.e., oxygen tension at which the Hb molecule is one-half saturated) is approximately 27 mmHg in normal erythrocytes (dotted lines). Heterotopic modifiers of Hb function can shift the curve leftward by increasing or rightward by decreasing its oxy gen affinity. BPG, Bisphosphoglycerate Pco2 , partial pressure of carbon dioxide; Po2, partial pressure of oxygen. (Reproduced with permission from Benz EJ, Jr. Synthesis, structure, and function of hemoglobin. In: Kelly WN, DeVita VT, eds. Textbook of Internal Medicine. vol 1. Philadelphia, PA: JB Lippincott; 1989:236.)

The poorly understood laws that govern the folding of proteins are responsible for the tertiary structure of globin, shown in Fig. 3. This folding pattern places polar residues exteriorly and provides a hydrophobic niche for the heme ring between the E and F helices. Numerous noncovalent bonds are formed between the heme and sur rounding amino acid residues of globin. An iron atom in the center of the porphyrin ring of heme forms an important bond with the F8 or proximal histidine and through the linked oxygen with the E7 or distal histidine residue. Oxygenation and deoxygenation of Hb occur at the heme iron. Folding of globin and association of chains into dimers and tetramers was once thought to occur spontaneously. However, it is now clear that these processes are assisted by chaperone proteins.

Two α-globin chains and two non-α-globin chains fit together specifically to form a Hb tetramer with a molecular mass of approximately 64,000 Da and with the quaternary structure shown in Fig. 4. The motion of individual globin chains, as well as the movement of globin chains relative to each other during oxygenation and deoxygenation, gives Hb its unique usefulness as a respiratory protein.

Fig4. QUATERNARY STRUCTURE OF HEMOGLOBIN. The contacts between subunits are shown as circled amino acids. In the front view (A), α1–β2 contacts are shown, and in the side view (B), α1-β–β1 contacts are depicted. (Reproduced with permission from Dickerson RE, Geis I. Hemoglobin: Structure, Function, and Evolution Pathology. Menlo Park, CA: Benjamin-Cummings; 1983.)

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علماء يبتكرون "آلية" تتوقع موعد ظهور أعراض الزهايمر

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الآخبار التكنلوجية

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المزيد

مواضيع ذات صلة

Hemoglobin Function

Phagocytes Ingest Target Cells

Cellular and Molecular Mechanisms in Development: Morphogens and Cell-to-Cell Signaling

Thrombopoietin Signaling

Mechanisms of Endomitosis in Megakaryocytes

Megakaryocytopoiesis

Ontogeny of Erythropoiesis

Cellular Dynamics in Erythropoiesis: Steady State and Stress Erythropoiesis

Erythropoiesis and Iron Regulation

Hematopoietic Microenvironment

Intrinsic Control of Erythropoiesis:Erythropoietin

Nuclear Organization