| Structural highlights
1cbm is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , ,
| | Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[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.[1] [2] [3] [4] 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.[5] 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.[6]
Function
[HBB_HUMAN] Involved in oxygen transport from the lung to the various peripheral tissues.[7] LVV-hemorphin-7 potentiates the activity of bradykinin, causing a decrease in blood pressure.[8]
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
The beta-chains isolated from the human hemoglobin alpha 2 beta 2 heterotetramer self-assemble to form a beta 4 homotetramer. We report the structure of the carbonmonoxy-beta 4 (CO beta 4) tetramer refined at a resolution of 1.8 A. Compared to the three known quaternary structures of human hemoglobin, the T state, the R state and the R2 state, the quaternary structure of CO beta 4 most closely resembles the R state. While the degree of structural similarity between CO beta 4 and the R state of liganded alpha 2 beta 2 is quite high, differences between the alpha and beta-chain sequences result in interesting alternative packing arrangements at the subunit interfaces of CO beta 4. In particular, Arg40 beta and Asp99 beta interact across the CO beta 4 equivalent of the alpha 1 beta 2 interface to form two symmetry-related salt bridges that have no counterpart in either liganded or deoxyhemoglobin. Because these salt bridges are near a 2-fold symmetry axis, steric constraints prevent their simultaneous formation, and electron density images of Arg40 beta and Asp99 beta show equally populated dual conformations for the side-chains of both residues. Relative to the liganded alpha 2 beta 2 tetramer, the Arg40 beta...Asp99 beta salt bridges introduce ionic interactions that should strengthen the CO beta 4 tetramer. The CO beta 4 equivalent of the alpha 1 alpha 2 and beta 1 beta 2 interfaces strengthens the tetramer relative to the liganded alpha 2 beta 2 tetramer by tethering both ends of the central cavity. (The entrance to the central cavity is altered so that the N termini move closer together and the C termini further apart, forming an anion binding pocket that is absent in liganded alpha 2 beta 2 hemoglobin.) In contrast, analysis of the CO beta 4 counterpart of the alpha 1 beta 1 interface indicates that this interface is weakened in the CO beta 4 tetramer. These differences in interface stability provide a structural explanation for the published observation that the alpha 2 beta 2 tetramer assembles via a stable alpha 1 beta 1 dimer intermediate, whereas assembly of the CO beta 4 tetramer is characterized more accurately by a monomer-tetramer equilibrium.
The 1.8 A structure of carbonmonoxy-beta 4 hemoglobin. Analysis of a homotetramer with the R quaternary structure of liganded alpha 2 beta 2 hemoglobin.,Borgstahl GE, Rogers PH, Arnone A J Mol Biol. 1994 Feb 25;236(3):817-30. PMID:8114096[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Borgstahl GE, Rogers PH, Arnone A. The 1.8 A structure of carbonmonoxy-beta 4 hemoglobin. Analysis of a homotetramer with the R quaternary structure of liganded alpha 2 beta 2 hemoglobin. J Mol Biol. 1994 Feb 25;236(3):817-30. PMID:8114096 doi:http://dx.doi.org/10.1006/jmbi.1994.1191
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