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'.
HBB interacts with Hemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans. The interaction is two-fold. Firstly, one HBB and one HBA1 combine to form a single polypetide chain (dimer). Secondly, two dimers combine to form a larger polypeptide (tetramer), and this becomes the functional haemolglobin.
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. 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 HBB, 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 falciparum in 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.
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 life-long 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.
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 the deadliest disease, and the 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.
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1a3o: ARTIFICIAL MUTANT (ALPHA Y42H) OF DEOXY HEMOGLOBIN
1abw: DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)
1aby: CYANOMET RHB1.1 (RECOMBINANT HEMOGLOBIN)
1aj9: R-STATE HUMAN CARBONMONOXYHEMOGLOBIN ALPHA-A53S
1b86: HUMAN DEOXYHAEMOGLOBIN-2,3-DIPHOSPHOGLYCERATE COMPLEX
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
1bbb: A THIRD QUATERNARY STRUCTURE OF HUMAN HEMOGLOBIN A AT 1.7-ANGSTROMS RESOLUTION
1bij: CROSSLINKED, DEOXY HUMAN HEMOGLOBIN A
1buw: CRYSTAL STRUCTURE OF S-NITROSO-NITROSYL HUMAN HEMOGLOBIN A
1bz0: HEMOGLOBIN A (HUMAN, DEOXY, HIGH SALT)
1bz1: HEMOGLOBIN (ALPHA + MET) VARIANT
1bzz: HEMOGLOBIN (ALPHA V1M) MUTANT
1c7b: DEOXY RHB1.0 (RECOMBINANT HEMOGLOBIN)
1c7c: DEOXY RHB1.1 (RECOMBINANT HEMOGLOBIN)
1c7d: DEOXY RHB1.2 (RECOMBINANT HEMOGLOBIN)
1cbl: THE 1.9 ANGSTROM STRUCTURE OF DEOXY-BETA4 HEMOGLOBIN: ANALYSIS OF THE PARTITIONING OF QUATERNARY-ASSOCIATED AND LIGAND-INDUCED CHANGES IN TERTIARY STRUCTURE
1cbm: THE 1.8 ANGSTROM STRUCTURE OF CARBONMONOXY-BETA4 HEMOGLOBIN: ANALYSIS OF A HOMOTETRAMER WITH THE R QUATERNARY STRUCTURE OF LIGANDED ALPHA2BETA2 HEMOGLOBIN
1cls: CROSS-LINKED HUMAN HEMOGLOBIN DEOXY
1cmy: THE MUTATION BETA99 ASP-TYR STABILIZES Y-A NEW, COMPOSITE QUATERNARY STATE OF HUMAN HEMOGLOBIN
1coh: STRUCTURE OF HAEMOGLOBIN IN THE DEOXY QUATERNARY STATE WITH LIGAND BOUND AT THE ALPHA HAEMS
1dke: NI BETA HEME HUMAN HEMOGLOBIN
1dxt: HIGH-RESOLUTION X-RAY STUDY OF DEOXY RECOMBINANT HUMAN HEMOGLOBINS SYNTHESIZED FROM BETA-GLOBINS HAVING MUTATED AMINO TERMINI
1dxu: HIGH-RESOLUTION X-RAY STUDY OF DEOXY RECOMBINANT HUMAN HEMOGLOBINS SYNTHESIZED FROM BETA-GLOBINS HAVING MUTATED AMINO TERMINI
1dxv: HIGH-RESOLUTION X-RAY STUDY OF DEOXY RECOMBINANT HUMAN HEMOGLOBINS SYNTHESIZED FROM BETA-GLOBINS HAVING MUTATED AMINO TERMINI
1fn3: CRYSTAL STRUCTURE OF NICKEL RECONSTITUTED HEMOGLOBIN-A CASE FOR PERMANENT, T-STATE HEMOGLOBIN
1g9v: HIGH RESOLUTION CRYSTAL STRUCTURE OF DEOXY HEMOGLOBIN COMPLEXED WITH A POTENT ALLOSTERIC EFFECTOR
1gbu: DEOXY (BETA-(C93A,C112G)) HUMAN HEMOGLOBIN
1gbv: (ALPHA-OXY, BETA-(C112G)DEOXY) T-STATE HUMAN HEMOGLOBIN
1gli: DEOXYHEMOGLOBIN T38W (ALPHA CHAINS), V1G (ALPHA AND BETA CHAINS)
1gzx: OXY T STATE HAEMOGLOBIN: OXYGEN BOUND AT ALL FOUR HAEMS
1hab: CROSSLINKED HAEMOGLOBIN
1hac: CROSSLINKED HAEMOGLOBIN
1hba: HIGH-RESOLUTION X-RAY STUDY OF DEOXYHEMOGLOBIN ROTHSCHILD 37BETA TRP-> ARG: A MUTATION THAT CREATES AN INTERSUBUNIT CHLORIDE-BINDING SITE
1hbb: HIGH-RESOLUTION X-RAY STUDY OF DEOXYHEMOGLOBIN ROTHSCHILD 37BETA TRP-> ARG: A MUTATION THAT CREATES AN INTERSUBUNIT CHLORIDE-BINDING SITE
1hbs: REFINED CRYSTAL STRUCTURE OF DEOXYHEMOGLOBIN S. I. RESTRAINED LEAST-SQUARES REFINEMENT AT 3.0-ANGSTROMS RESOLUTION
1hco: THE STRUCTURE OF HUMAN CARBONMONOXY HAEMOGLOBIN AT 2.7 ANGSTROMS RESOLUTION
1hdb: ANALYSIS OF THE CRYSTAL STRUCTURE, MOLECULAR MODELING AND INFRARED SPECTROSCOPY OF THE DISTAL BETA-HEME POCKET VALINE67(E11)-THREONINE MUTATION OF HEMOGLOBIN
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
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
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
1hho: STRUCTURE OF HUMAN OXYHAEMOGLOBIN AT 2.1 ANGSTROMS RESOLUTION
1ird: Crystal Structure of Human Carbonmonoxy-Haemoglobin at 1.25 A Resolution
1j3y: Direct observation of photolysis-induced tertiary structural changes in human hemoglobin; Crystal structure of alpha(Fe)-beta(Ni) hemoglobin (laser photolysed)
1j3z: Direct observation of photolysis-induced tertiary structural changes in human haemoglobin; Crystal structure of alpha(Fe-CO)-beta(Ni) hemoglobin (laser unphotolysed)
1j40: Direct observation of photolysis-induced tertiary structural changes in human haemoglobin; Crystal structure of alpha(Ni)-beta(Fe-CO) hemoglobin (laser unphotolysed)
1j41: Direct observation of photolysis-induced tertiary structural changes in human haemoglobin; Crystal structure of alpha(Ni)-beta(Fe) hemoglobin (laser photolysed)
1j7s: Crystal Structure of deoxy HbalphaYQ, a mutant of HbA
1j7w: Crystal structure of deoxy HbbetaYQ, a site directed mutant of HbA
1j7y: Crystal structure of partially ligated mutant of HbA
1jy7: THE STRUCTURE OF HUMAN METHEMOGLOBIN. THE VARIATION OF A THEME
1k0y: X-ray Crystallographic Analyses of Symmetrical Allosteric Effectors of Hemoglobin. Compounds Designed to Link Primary and Secondary Binding Sites
1k1k: Structure of Mutant Human Carbonmonoxyhemoglobin C (beta E6K) at 2.0 Angstrom Resolution in Phosphate Buffer.
1kd2: Crystal Structure of Human Deoxyhemoglobin in Absence of Any Anions
1lfl: DEOXY HEMOGLOBIN (90% RELATIVE HUMIDITY)
1lfq: OXY HEMOGLOBIN (93% RELATIVE HUMIDITY)
1lft: OXY HEMOGLOBIN (90% RELATIVE HUMIDITY)
1lfv: OXY HEMOGLOBIN (88% RELATIVE HUMIDITY)
1lfy: OXY HEMOGLOBIN (84% RELATIVE HUMIDITY)
1lfz: OXY HEMOGLOBIN (25% METHANOL)
1ljw: Crystal Structure of Human Carbonmonoxy Hemoglobin at 2.16 A: A Snapshot of the Allosteric Transition
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
1mko: A Fourth Quaternary Structure of Human Hemoglobin A at 2.18 A Resolution
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
1nih: Structure of deoxy-quaternary haemoglobin with liganded beta subunits
1nqp: Crystal structure of Human hemoglobin E at 1.73 A resolution