| Structural highlights
Disease
[HBA_HUMAN] Defects in HBA1 may be a cause of Heinz body anemias (HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.[1] Defects in HBA1 are the cause of alpha-thalassemia (A-THAL) [MIM:604131]. The thalassemias are the most common monogenic diseases and occur mostly in Mediterranean and Southeast Asian populations. The hallmark of alpha-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. The level of alpha chain production can range from none to very nearly normal levels. Deletion of both copies of each of the two alpha-globin genes causes alpha(0)-thalassemia, also known as homozygous alpha thalassemia. Due to the complete absence of alpha chains, the predominant fetal hemoglobin is a tetramer of gamma-chains (Bart hemoglobin) that has essentially no oxygen carrying capacity. This causes oxygen starvation in the fetal tissues leading to prenatal lethality or early neonatal death. The loss of three alpha genes results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia known as hemoglobin H disease. Untreated, most patients die in childhood or early adolescence. The loss of two alpha genes results in mild alpha-thalassemia, also known as heterozygous alpha-thalassemia. Affected individuals have small red cells and a mild anemia (microcytosis). If three of the four alpha-globin genes are functional, individuals are completely asymptomatic. Some rare forms of alpha-thalassemia are due to point mutations (non-deletional alpha-thalassemia). The thalassemic phenotype is due to unstable globin alpha chains that are rapidly catabolized prior to formation of the alpha-beta heterotetramers. Note=Alpha(0)-thalassemia is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. Defects in HBA1 are the cause of hemoglobin H disease (HBH) [MIM:613978]. HBH is a form of alpha-thalassemia due to the loss of three alpha genes. This results in high levels of a tetramer of four beta chains (hemoglobin H), causing a severe and life-threatening anemia. Untreated, most patients die in childhood or early adolescence.[2] [HBB_HUMAN] Defects in HBB may be a cause of Heinz body anemias (HEIBAN) [MIM:140700]. This is a form of non-spherocytic hemolytic anemia of Dacie type 1. After splenectomy, which has little benefit, basophilic inclusions called Heinz bodies are demonstrable in the erythrocytes. Before splenectomy, diffuse or punctate basophilia may be evident. Most of these cases are probably instances of hemoglobinopathy. The hemoglobin demonstrates heat lability. Heinz bodies are observed also with the Ivemark syndrome (asplenia with cardiovascular anomalies) and with glutathione peroxidase deficiency.[3] [4] [5] [6] Defects in HBB are the cause of beta-thalassemia (B-THAL) [MIM:613985]. A form of thalassemia. Thalassemias are common monogenic diseases occurring mostly in Mediterranean and Southeast Asian populations. The hallmark of beta-thalassemia is an imbalance in globin-chain production in the adult HbA molecule. Absence of beta chain causes beta(0)-thalassemia, while reduced amounts of detectable beta globin causes beta(+)-thalassemia. In the severe forms of beta-thalassemia, the excess alpha globin chains accumulate in the developing erythroid precursors in the marrow. Their deposition leads to a vast increase in erythroid apoptosis that in turn causes ineffective erythropoiesis and severe microcytic hypochromic anemia. Clinically, beta-thalassemia is divided into thalassemia major which is transfusion dependent, thalassemia intermedia (of intermediate severity), and thalassemia minor that is asymptomatic.[7] Defects in HBB are the cause of sickle cell anemia (SKCA) [MIM:603903]; also known as sickle cell disease. Sickle cell anemia is characterized by abnormally shaped red cells resulting in chronic anemia and periodic episodes of pain, serious infections and damage to vital organs. Normal red blood cells are round and flexible and flow easily through blood vessels, but in sickle cell anemia, the abnormal hemoglobin (called Hb S) causes red blood cells to become stiff. They are C-shaped and resembles a sickle. These stiffer red blood cells can led to microvascular occlusion thus cutting off the blood supply to nearby tissues. Defects in HBB are the cause of beta-thalassemia dominant inclusion body type (B-THALIB) [MIM:603902]. An autosomal dominant form of beta thalassemia characterized by moderate anemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphologic changes in the red cells, erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow and in the peripheral blood after splenectomy.[8]
Function
[HBA_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues. [HBB_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues.[9] LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.[10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
BACKGROUND:. Potential blood substitutes can be based on hemoglobin. Two problems must be overcome with acellular hemoglobin-based blood substitutes, however: the oxygen affinity of purified human hemoglobin is too high for it to deliver oxygen to tissues, and hemoglobin tetramers dissociate into alphabeta dimers that can cause kidney damage. A modified form of hemoglobin, rHb 1.1, has reduced oxygen affinity as the result of an Asnbeta 108-->Lys mutation, and dimerization is prevented by the insertion of a glycine residue between the sequences of the normal alpha chains to produce one covalently continuous di-alpha-chain. Determination of the structure of rHb 1.1 would provide structure-based explanations for the altered properties of rHb 1.1. RESULTS:. We determined the structures of the deoxy form of rHb 1.1 at 2.0 resolution and of cyanomet-rHb 1.1 at 2.6 resolution. Deoxy-rHb 1.1 adopts the classic 'T state' quaternary structure, but cyanomet-rHb 1.1 adopts a novel quanternary structure, the B state. The most striking feature of the tertiary structures is a charged hydrogen bond involving Lysbeta 108 that is broken in the T-->B state transition. The glycine bridge within the di-alpha-chain is well defined in both structures and appears to cause adoption of the B state instead of the previously observed ligand-bound quaternary structures R or Y/R2. CONCLUSIONS:. A charged hydrogen bond between Lysbeta 108 and Tyrbeta35 is broken in the transition between the deoxy and ligand-bound forms of rHb 1.1. This structural change reduces the oxygen affinity of rHb 1.1 by changing the relative stability of deoxy and ligand-bound states. Furthermore, our observations highlight the importance of small conformational changes in allosteric proteins, even in their most rigid domains. Three ligand-bound quaternary structures of hemoglobin (R, Y/R2 and B) have now been described. In contrast, only one quaternary structure has been observed for deoxyhemoglobin (T). The structural degeneracy of the high oxygen affinity form of hemoglobin is an important reminder that allosteric proteins may have multiple quaternary structures that are functionally very similar. This degeneracy of quaternary structures has important implications for the regulation of allosteric proteins, because different quaternary structures may be stabilized by different allosteric effectors.
Structures of a hemoglobin-based blood substitute: insights into the function of allosteric proteins.,Kroeger KS, Kundrot CE Structure. 1997 Feb 15;5(2):227-37. PMID:9032082[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ohba Y, Yamamoto K, Hattori Y, Kawata R, Miyaji T. Hyperunstable hemoglobin Toyama [alpha 2 136(H19)Leu----Arg beta 2]: detection and identification by in vitro biosynthesis with radioactive amino acids. Hemoglobin. 1987;11(6):539-56. PMID:2833478
- ↑ Traeger-Synodinos J, Harteveld CL, Kanavakis E, Giordano PC, Kattamis C, Bernini LF. Hb Aghia Sophia [alpha62(E11)Val-->0 (alpha1)], an "in-frame" deletion causing alpha-thalassemia. Hemoglobin. 1999 Nov;23(4):317-24. PMID:10569720
- ↑ Thillet J, Cohen-Solal M, Seligmann M, Rosa J. Functional and physicochemical studies of hemoglobin St. Louis beta 28 (B10) Leu replaced by Gln: a variant with ferric beta heme iron. J Clin Invest. 1976 Nov;58(5):1098-1106. PMID:186485 doi:http://dx.doi.org/10.1172/JCI108561
- ↑ Rahbar S, Feagler RJ, Beutler E. Hemoglobin Hammersmith (beta 42 (CD1) Phe replaced by Ser) associated with severe hemolytic anemia. Hemoglobin. 1981;5(1):97-105. PMID:6259091
- ↑ Blouquit Y, Bardakdjian J, Lena-Russo D, Arous N, Perrimond H, Orsini A, Rosa J, Galacteros F. Hb Bruxelles: alpha 2A beta (2)41 or 42(C7 or CD1)Phe deleted. Hemoglobin. 1989;13(5):465-74. PMID:2599881
- ↑ Rees DC, Rochette J, Schofield C, Green B, Morris M, Parker NE, Sasaki H, Tanaka A, Ohba Y, Clegg JB. A novel silent posttranslational mechanism converts methionine to aspartate in hemoglobin Bristol (beta 67[E11] Val-Met->Asp). Blood. 1996 Jul 1;88(1):341-8. PMID:8704193
- ↑ Thein SL, Hesketh C, Taylor P, Temperley IJ, Hutchinson RM, Old JM, Wood WG, Clegg JB, Weatherall DJ. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc Natl Acad Sci U S A. 1990 May;87(10):3924-8. PMID:1971109
- ↑ Thein SL, Hesketh C, Taylor P, Temperley IJ, Hutchinson RM, Old JM, Wood WG, Clegg JB, Weatherall DJ. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc Natl Acad Sci U S A. 1990 May;87(10):3924-8. PMID:1971109
- ↑ Ianzer D, Konno K, Xavier CH, Stocklin R, Santos RA, de Camargo AC, Pimenta DC. Hemorphin and hemorphin-like peptides isolated from dog pancreas and sheep brain are able to potentiate bradykinin activity in vivo. Peptides. 2006 Nov;27(11):2957-66. Epub 2006 Aug 9. PMID:16904236 doi:S0196-9781(06)00309-3
- ↑ Ianzer D, Konno K, Xavier CH, Stocklin R, Santos RA, de Camargo AC, Pimenta DC. Hemorphin and hemorphin-like peptides isolated from dog pancreas and sheep brain are able to potentiate bradykinin activity in vivo. Peptides. 2006 Nov;27(11):2957-66. Epub 2006 Aug 9. PMID:16904236 doi:S0196-9781(06)00309-3
- ↑ Kroeger KS, Kundrot CE. Structures of a hemoglobin-based blood substitute: insights into the function of allosteric proteins. Structure. 1997 Feb 15;5(2):227-37. PMID:9032082
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