In human, the HBB gene is located on chromosome 11 at position p15.5.
Beta globin (also referred to as HBB, β-globin, haemoglobin beta, hemoglobin beta, or preferably haemoglobin subunit beta) is a globinprotein, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, the HbA. It is 146 amino acids long and has a molecular weight of 15,867 Da. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains.
HBB protein is produced by the gene HBB which is located in the multigene locus of β-globin locus on chromosome 11, specifically on the short arm position 15.5. Expression of beta globin and the neighbouring globins in the β-globin locus is controlled by single locus control region (LCR), the most important regulatory element in the locus located upstream of the globin genes. The normal allelic variant is 1600 base pairs (bp) long and contains three exons. The order of the genes in the beta-globin cluster is 5' - epsilon – gamma-G – gamma-A – delta – beta - 3'.
"DNA sequence analysis of a cloned β-globin gene from a Chinese patient with β-thalassemia revealed a single nucleotide substitution (A→ G) within the ATA box homology and 28 base pairs upstream from the cap site."
"Comparison of the level of β-globin transcripts in a variety of deletion mutants shows that for efficient transcription, both the ATA or Goldberg–Hogness box, and a region between 100 and 58 base pairs in front of the site at which transcription is initiated, are required. Deletion of either of these regions results in a decrease in the level of β-globin transcripts by an order of magnitude; deletion of the ATA box causes an additional loss in the specificity of the site of initiation of RNA synthesis. The DNA sequences downstream from the ATA box, including the natural β-globin mRNA cap site, are dispensable for transcription in vivo."
"The first is a sequence rich in the nucleic acids adenine and thymine (the Goldberg-Hogness, "TATA," or "ATA" box) which is located 20-30 base pairs upstream from the RNA initiation site (the cap site which is the transcriptional start site for the mRNA) and is characterized by a concensus sequence (5'-TATAA-ATA-3')."
GeneID: 3043 HBB hemoglobin subunit beta, "The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'."
HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans. The interaction is two-fold. First, one HBB and one HBA1 combine, non-covalently, to form a dimer. Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemolglobin.
Associated genetic disorders
Total or partial absence of HBB causes a genetic disease called beta thalassemia. Total loss called, thalassemia major or beta-0-thalassemia, is due to mutation in both alleles, and this results in failure to form beta chain of haemoglobin. It prevents oxygen supply in the tissues. It is highly lethal. Symptoms, such as severe anaemia and heart attack, appear within two years after birth. They can be treated only by lifelong blood transfusion and bone marrow transplantation. Reduced HBB function called thalassemia minor or beta+ thalassemia is due to mutation in one of the alleles. It is less severe but patients are prone to other diseases such as asthma and liver problems.
According to a recent study, the stop gain mutation Gln40stop in HBB gene is a common cause of autosomal recessiveBeta- thalassemia in Sardinian people (almost exclusive in Sardinia). Carriers of this mutation show an enhanced red blood cell count. As a curiosity, the same mutation was also associated to a decrease in serum LDL levels in carriers, so the authors suggest that is due to the need of cholesterol to regenerate cell membranes.
Sickle cell disease
More than a thousand naturally occurring HBB variants have been discovered. The most common is HbS, which causes sickle cell disease. HbS is produced by a point mutation in HBB in which the codon GAG is replaced by GTG. This results in the replacement of hydrophilic amino acid glutamic acid with the hydrophobic amino acid valine at the sixth position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent haemoglobin molecule's beta chain. This further causes clumping of HbS molecules into rigid fibers, causing "sickling" of the entire red blood cells in the homozygous (HbS/HbS) condition. The homozygous allele has become one of the deadliest genetic factors. Whereas, people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia.
Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together. HbC mutation is at the same position in HbS, but glutamic acid is replaced by lysine (β6Glu→Lys). The mutation is particularly prevalent in West African populations. HbC provides near full protection against Plasmodium falciparumin homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals. This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions.
Another point mutation in HBB, in which glutamic acid is replaced with lysine at position 26 (β26Glu→Lys), leads to the formation of haemoglobin E (HbE). HbE has a very unstable α- and β-globin association. Even though the unstable protein itself has mild effect, inherited with HbS and thalassemia traits, it turns into a life-threatening form of β-thalassemia. The mutation is of relatively recent origin suggesting that it resulted from selective pressure against severe falciparum malaria, as heterozygous allele prevents the development of malaria.
Malaria due to Plasmodium falciparum is a major selective factor in human evolution. It has influenced mutations in HBB in various degrees resulting in the existence of numerous HBB variants. Some of these mutations are not directly lethal and instead confer resistance to malaria, particularly in Africa where malaria is epidemic. People of African descent have evolved to have higher rates of the mutant HBB because the heterozygous individuals have a misshaped red blood cell that prevent attacks from malarial parasites. Thus, HBB mutants are the sources of positive selection in these regions and are important for their long-term survival. Such selection markers are important for tracing human ancestry and diversification from Africa.
↑Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–968. doi:10.1016/j.cell.2005.08.029. PMID16169070.
↑Muncie HL, Campbell J (2009). "Alpha and beta thalassemia". American Family Physician. 80 (4): 339–44. PMID19678601.
↑"Beta thalassemia". Genetics Home Reference. U.S. National Library of Medicine. 11 November 2014. Retrieved 18 November 2014.
↑Valenti L, Canavesi E, Galmozzi E, Dongiovanni P, Rametta R, Maggioni P, Maggioni M, Fracanzani AL, Fargion S (2010). "Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease". Journal of Hepatology. 53 (5): 927–933. doi:10.1016/j.jhep.2010.05.023. PMID20739079.
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↑Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M (2001). "Haemoglobin C protects against clinical Plasmodium falciparum malaria". Nature. 414 (6861): 305–308. doi:10.1038/35104556. PMID11713529.
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↑Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S, White N (2002). "Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria". Blood. 100 (4): 1172–1176. PMID12149194.
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1a3o: ARTIFICIAL MUTANT (ALPHA Y42H) OF DEOXY HEMOGLOBIN
PDB 1abw EBI.jpg
1abw: DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)
PDB 1aby EBI.jpg
1aby: CYANOMET RHB1.1 (RECOMBINANT HEMOGLOBIN)
PDB 1aj9 EBI.jpg
1aj9: R-STATE HUMAN CARBONMONOXYHEMOGLOBIN ALPHA-A53S
PDB 1b86 EBI.jpg
1b86: HUMAN DEOXYHAEMOGLOBIN-2,3-DIPHOSPHOGLYCERATE COMPLEX
PDB 1bab EBI.jpg
1bab: HEMOGLOBIN THIONVILLE: AN ALPHA-CHAIN VARIANT WITH A SUBSTITUTION OF A GLUTAMATE FOR VALINE AT NA-1 AND HAVING AN ACETYLATED METHIONINE NH2 TERMINUS
PDB 1bbb EBI.jpg
1bbb: A THIRD QUATERNARY STRUCTURE OF HUMAN HEMOGLOBIN A AT 1.7-ANGSTROMS RESOLUTION
PDB 1bij EBI.jpg
1bij: CROSSLINKED, DEOXY HUMAN HEMOGLOBIN A
PDB 1buw EBI.jpg
1buw: CRYSTAL STRUCTURE OF S-NITROSO-NITROSYL HUMAN HEMOGLOBIN A
PDB 1bz0 EBI.jpg
1bz0: HEMOGLOBIN A (HUMAN, DEOXY, HIGH SALT)
PDB 1bz1 EBI.jpg
1bz1: HEMOGLOBIN (ALPHA + MET) VARIANT
PDB 1bzz EBI.jpg
1bzz: HEMOGLOBIN (ALPHA V1M) MUTANT
PDB 1c7b EBI.jpg
1c7b: DEOXY RHB1.0 (RECOMBINANT HEMOGLOBIN)
PDB 1c7c EBI.jpg
1c7c: DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)
PDB 1c7d EBI.jpg
1c7d: DEOXY RHB1.2 (RECOMBINANT HEMOGLOBIN)
PDB 1cbl EBI.jpg
1cbl: THE 1.9 ANGSTROM STRUCTURE OF DEOXY-BETA4 HEMOGLOBIN: ANALYSIS OF THE PARTITIONING OF QUATERNARY-ASSOCIATED AND LIGAND-INDUCED CHANGES IN TERTIARY STRUCTURE
PDB 1cbm EBI.jpg
1cbm: THE 1.8 ANGSTROM STRUCTURE OF CARBONMONOXY-BETA4 HEMOGLOBIN: ANALYSIS OF A HOMOTETRAMER WITH THE R QUATERNARY STRUCTURE OF LIGANDED ALPHA2BETA2 HEMOGLOBIN
PDB 1cls EBI.jpg
1cls: CROSS-LINKED HUMAN HEMOGLOBIN DEOXY
PDB 1cmy EBI.jpg
1cmy: THE MUTATION BETA99 ASP-TYR STABILIZES Y-A NEW, COMPOSITE QUATERNARY STATE OF HUMAN HEMOGLOBIN
PDB 1coh EBI.jpg
1coh: STRUCTURE OF HAEMOGLOBIN IN THE DEOXY QUATERNARY STATE WITH LIGAND BOUND AT THE ALPHA HAEMS
PDB 1dke EBI.jpg
1dke: NI BETA HEME HUMAN HEMOGLOBIN
PDB 1dxt EBI.jpg
1dxt: HIGH-RESOLUTION X-RAY STUDY OF DEOXY RECOMBINANT HUMAN HEMOGLOBINS SYNTHESIZED FROM BETA-GLOBINS HAVING MUTATED AMINO TERMINI
PDB 1dxu EBI.jpg
1dxu: HIGH-RESOLUTION X-RAY STUDY OF DEOXY RECOMBINANT HUMAN HEMOGLOBINS SYNTHESIZED FROM BETA-GLOBINS HAVING MUTATED AMINO TERMINI
PDB 1dxv EBI.jpg
1dxv: HIGH-RESOLUTION X-RAY STUDY OF DEOXY RECOMBINANT HUMAN HEMOGLOBINS SYNTHESIZED FROM BETA-GLOBINS HAVING MUTATED AMINO TERMINI
PDB 1fn3 EBI.jpg
1fn3: CRYSTAL STRUCTURE OF NICKEL RECONSTITUTED HEMOGLOBIN-A CASE FOR PERMANENT, T-STATE HEMOGLOBIN
PDB 1g9v EBI.jpg
1g9v: HIGH RESOLUTION CRYSTAL STRUCTURE OF DEOXY HEMOGLOBIN COMPLEXED WITH A POTENT ALLOSTERIC EFFECTOR
PDB 1gbu EBI.jpg
1gbu: DEOXY (BETA-(C93A,C112G)) HUMAN HEMOGLOBIN
PDB 1gbv EBI.jpg
1gbv: (ALPHA-OXY, BETA-(C112G)DEOXY) T-STATE HUMAN HEMOGLOBIN
PDB 1gli EBI.jpg
1gli: DEOXYHEMOGLOBIN T38W (ALPHA CHAINS), V1G (ALPHA AND BETA CHAINS)
PDB 1gzx EBI.jpg
1gzx: OXY T STATE HAEMOGLOBIN: OXYGEN BOUND AT ALL FOUR HAEMS
PDB 1hab EBI.jpg
1hab: CROSSLINKED HAEMOGLOBIN
PDB 1hac EBI.jpg
1hac: CROSSLINKED HAEMOGLOBIN
PDB 1hba EBI.jpg
1hba: HIGH-RESOLUTION X-RAY STUDY OF DEOXYHEMOGLOBIN ROTHSCHILD 37BETA TRP-> ARG: A MUTATION THAT CREATES AN INTERSUBUNIT CHLORIDE-BINDING SITE
PDB 1hbb EBI.jpg
1hbb: HIGH-RESOLUTION X-RAY STUDY OF DEOXYHEMOGLOBIN ROTHSCHILD 37BETA TRP-> ARG: A MUTATION THAT CREATES AN INTERSUBUNIT CHLORIDE-BINDING SITE
PDB 1hbs EBI.jpg
1hbs: REFINED CRYSTAL STRUCTURE OF DEOXYHEMOGLOBIN S. I. RESTRAINED LEAST-SQUARES REFINEMENT AT 3.0-ANGSTROMS RESOLUTION
PDB 1hco EBI.jpg
1hco: THE STRUCTURE OF HUMAN CARBONMONOXY HAEMOGLOBIN AT 2.7 ANGSTROMS RESOLUTION
PDB 1hdb EBI.jpg
1hdb: ANALYSIS OF THE CRYSTAL STRUCTURE, MOLECULAR MODELING AND INFRARED SPECTROSCOPY OF THE DISTAL BETA-HEME POCKET VALINE67(E11)-THREONINE MUTATION OF HEMOGLOBIN
PDB 1hga EBI.jpg
1hga: HIGH RESOLUTION CRYSTAL STRUCTURES AND COMPARISONS OF T STATE DEOXYHAEMOGLOBIN AND TWO LIGANDED T-STATE HAEMOGLOBINS: T(ALPHA-OXY)HAEMOGLOBIN AND T(MET)HAEMOGLOBIN
PDB 1hgb EBI.jpg
1hgb: HIGH RESOLUTION CRYSTAL STRUCTURES AND COMPARISONS OF T STATE DEOXYHAEMOGLOBIN AND TWO LIGANDED T-STATE HAEMOGLOBINS: T(ALPHA-OXY)HAEMOGLOBIN AND T(MET)HAEMOGLOBIN
PDB 1hgc EBI.jpg
1hgc: HIGH RESOLUTION CRYSTAL STRUCTURES AND COMPARISONS OF T STATE DEOXYHAEMOGLOBIN AND TWO LIGANDED T-STATE HAEMOGLOBINS: T(ALPHA-OXY)HAEMOGLOBIN AND T(MET)HAEMOGLOBIN
PDB 1hho EBI.jpg
1hho: STRUCTURE OF HUMAN OXYHAEMOGLOBIN AT 2.1 ANGSTROMS RESOLUTION
PDB 1ird EBI.jpg
1ird: Crystal Structure of Human Carbonmonoxy-Haemoglobin at 1.25 A Resolution
PDB 1j3y EBI.jpg
1j3y: Direct observation of photolysis-induced tertiary structural changes in human hemoglobin; Crystal structure of alpha(Fe)-beta(Ni) hemoglobin (laser photolysed)
PDB 1j3z EBI.jpg
1j3z: Direct observation of photolysis-induced tertiary structural changes in human haemoglobin; Crystal structure of alpha(Fe-CO)-beta(Ni) hemoglobin (laser unphotolysed)
PDB 1j40 EBI.jpg
1j40: Direct observation of photolysis-induced tertiary structural changes in human haemoglobin; Crystal structure of alpha(Ni)-beta(Fe-CO) hemoglobin (laser unphotolysed)
PDB 1j41 EBI.jpg
1j41: Direct observation of photolysis-induced tertiary structural changes in human haemoglobin; Crystal structure of alpha(Ni)-beta(Fe) hemoglobin (laser photolysed)
PDB 1j7s EBI.jpg
1j7s: Crystal Structure of deoxy HbalphaYQ, a mutant of HbA
PDB 1j7w EBI.jpg
1j7w: Crystal structure of deoxy HbbetaYQ, a site directed mutant of HbA
PDB 1j7y EBI.jpg
1j7y: Crystal structure of partially ligated mutant of HbA
PDB 1jy7 EBI.jpg
1jy7: THE STRUCTURE OF HUMAN METHEMOGLOBIN. THE VARIATION OF A THEME
PDB 1k0y EBI.jpg
1k0y: X-ray Crystallographic Analyses of Symmetrical Allosteric Effectors of Hemoglobin. Compounds Designed to Link Primary and Secondary Binding Sites
PDB 1k1k EBI.jpg
1k1k: Structure of Mutant Human Carbonmonoxyhemoglobin C (beta E6K) at 2.0 Angstrom Resolution in Phosphate Buffer.
PDB 1kd2 EBI.jpg
1kd2: Crystal Structure of Human Deoxyhemoglobin in Absence of Any Anions
PDB 1lfl EBI.jpg
1lfl: DEOXY HEMOGLOBIN (90% RELATIVE HUMIDITY)
PDB 1lfq EBI.jpg
1lfq: OXY HEMOGLOBIN (93% RELATIVE HUMIDITY)
PDB 1lft EBI.jpg
1lft: OXY HEMOGLOBIN (90% RELATIVE HUMIDITY)
PDB 1lfv EBI.jpg
1lfv: OXY HEMOGLOBIN (88% RELATIVE HUMIDITY)
PDB 1lfy EBI.jpg
1lfy: OXY HEMOGLOBIN (84% RELATIVE HUMIDITY)
PDB 1lfz EBI.jpg
1lfz: OXY HEMOGLOBIN (25% METHANOL)
PDB 1ljw EBI.jpg
1ljw: Crystal Structure of Human Carbonmonoxy Hemoglobin at 2.16 A: A Snapshot of the Allosteric Transition
PDB 1m9p EBI.jpg
1m9p: Crystalline Human Carbonmonoxy Hemoglobin C Exhibits The R2 Quaternary State at Neutral pH In The Presence of Polyethylene Glycol: The 2.1 Angstrom Resolution Crystal Structure
PDB 1mko EBI.jpg
1mko: A Fourth Quaternary Structure of Human Hemoglobin A at 2.18 A Resolution
PDB 1nej EBI.jpg
1nej: Crystalline Human Carbonmonoxy Hemoglobin S (Liganded Sickle Cell Hemoglobin) Exhibits The R2 Quaternary State At Neutral pH In The Presence Of Polyethylene Glycol: The 2.1 Angstrom Resolution Crystal Structure
PDB 1nih EBI.jpg
1nih: Structure of deoxy-quaternary haemoglobin with liganded beta subunits
PDB 1nqp EBI.jpg
1nqp: Crystal structure of Human hemoglobin E at 1.73 A resolution