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Hemoglobin subunit beta
Hemoglobin subunit beta
Hemoglobin subunit beta
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"HBB" redirects here. For other uses, see HBB (disambiguation).
HBB
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesHBB, CD113t-C, beta-globin, hemoglobin subunit beta, ECYT6
External IDsOMIM: 141900; MGI: 5474850; HomoloGene: 68066; GeneCards: HBB; OMA:HBB - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3043

101488143

Ensembl

ENSG00000244734

ENSMUSG00000073940

UniProt

P68871

P02088

RefSeq (mRNA)

NM_000518

NM_008220

RefSeq (protein)

NP_000509

NP_032246
NP_001188320
NP_001265090

Location (UCSC)Chr 11: 5.23 – 5.23 MbChr 7: 103.46 – 103.46 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse
In human, the HBB gene is located on chromosome 11 at position p15.5.

Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the HBB gene, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, hemoglobin A (HbA).[5] It is 147 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.

β-globin is encoded by the HBB gene on human chromosome 11. Mutations in the gene produce several variants of the proteins which are implicated with genetic disorders such as sickle-cell disease and beta thalassemia, as well as beneficial traits such as genetic resistance to malaria.[6][7] At least 50 disease-causing mutations in this gene have been discovered.[8]

Gene locus

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Main article: Human β-globin locus

Beta-globin 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 15.4. 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.[9] 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'.[5]

Interactions

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Beta-globin interacts with alpha-globin to form haemoglobin A, the major haemoglobin in adult humans.[10][11] The interaction is two-fold. First, one β-globin molecule and one α-globin molecule combine by electrostatic attraction to form a dimer.[12] Secondly, two dimers combine to form the four-chain tetramer, and this becomes the functional haemoglobin.[13]

Associated genetic disorders

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Beta thalassemia

[edit]
Main article: Beta thalassemia

Beta thalassemia is an inherited genetic mutation in one (Beta thalassemia minor) or both (Beta thalassemia major) of the Beta globin alleles on chromosome 11. The mutant alleles are subdivided into two groups: β0, in which no functional β-globin is made, and β+, in which a small amount of normal β-globin protein is produced. Beta thalassemia minor occurs when an individual inherits one normal Beta allele and one abnormal Beta allele (either β0, or β+). Beta thalassemia minor results in a mild microcytic anemia that is often asymptomatic or may cause fatigue and or pale skin. Beta thalassemia major occurs when a person inherits two abnormal alleles. This can be either two β+ alleles, two β0 alleles, or one of each. Beta thalassemia major is a severe medical condition. A severe anemia is seen starting at 6 months of age. Without medical treatment death often occurs before age 12.[14] Beta thalassemia major can be treated by lifelong blood transfusions or bone marrow transplantation.[15][16]

Sickle cell disease

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Main article: 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 seventh position (β6Glu→Val). This substitution creates a hydrophobic spot on the outside of the protein that sticks to the hydrophobic region of an adjacent hemoglobin 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.[17] The homozygous allele has become one of the deadliest genetic factors,[18] whereas people heterozygous for the mutant allele (HbS/HbA) are resistant to malaria and develop minimal effects of the anaemia.[19]

Haemoglobin C

[edit]
Main article: Hemoglobin C

Sickle cell disease is closely related to another mutant haemoglobin called haemoglobin C (HbC), because they can be inherited together.[20] 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 falciparum in homozygous (CC) individuals and intermediate protection in heterozygous (AC) individuals.[21] This indicates that HbC has stronger influence than HbS, and is predicted to replace HbS in malaria-endemic regions.[22]

Haemoglobin E

[edit]
Main article: Hemoglobin E

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).[23] 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.[24]

Human evolution

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Main article: Malaria resistance

Malaria due to Plasmodium falciparum is a major selective factor in human evolution.[7][25] 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 parts of the world where malaria is epidemic.[26][27] For example, there is evidence that the sickle cell mutation, common in people of African descent, provides a degree of resistance to severe malaria.[28] Thus, HBB mutations are the sources of positive selection in these regions and are important for their long-term survival.[6][29] Such selection markers are important for tracing human ancestry and diversification from Africa.[30]

See also

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References

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Further reading

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[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Hemoglobin subunit beta

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from Grokipedia
Hemoglobin subunit beta, also known as beta-globin, is a encoded by the HBB gene located on the short arm of at position 11p15.4, serving as one of the two β-chains in the tetrameric structure of adult (HbA), which consists of two α-chains and two β-chains (α₂β₂). This subunit is essential for the primary function of in red blood cells, where it binds to a prosthetic group containing iron to facilitate the reversible binding and transport of oxygen from the lungs to tissues throughout the body, while also aiding in excretion. The HBB gene spans approximately 1.6 kilobases and contains three exons, producing a 146-amino-acid polypeptide that is synthesized postnatally, replacing fetal γ-globin chains to form the predominant adult hemoglobin variant, which constitutes about 97% of total in healthy adults. Structurally, the beta subunit adopts a folded conformation with eight α-helices (designated A through H) that enclose the heme group in a hydrophobic pocket, enabling oxygen coordination to the iron atom at the distal histidine (His E7) position and allowing for cooperative binding across the tetramer. The subunit's interactions at the α₁β₁ and α₁β₂ interfaces contribute to hemoglobin's allosteric regulation, transitioning between a low-affinity tense (T) state and a high-affinity relaxed (R) state upon oxygen binding, with additional modulation by heterotropic effectors such as 2,3-bisphosphoglycerate (2,3-BPG), protons, and carbon dioxide to fine-tune oxygen delivery under varying physiological conditions. This dynamic quaternary structure ensures efficient oxygen transport, with the beta chains playing a key role in the Bohr effect, where decreased pH or increased CO₂ levels promote oxygen release in metabolically active tissues. Mutations in the HBB gene are associated with several significant hemoglobinopathies, including caused by a Glu6Val substitution (HbS) that promotes of deoxygenated hemoglobin into rigid fibers, leading to vaso-occlusive crises, chronic , and organ damage. Beta-thalassemia arises from over 300 variants that reduce or abolish beta-globin production, resulting in excess α-chains that precipitate and cause ineffective , severe , and in transfusion-dependent cases. Other HBB alterations, such as those in (beta-globin type), impair iron , reducing oxygen-carrying capacity and causing , while certain polymorphisms confer against in endemic regions.

Molecular Structure and Biochemistry

Primary and Secondary Structure

The hemoglobin subunit beta (HBB), also known as beta-globin, is a polypeptide chain consisting of 146 amino acids in its mature form, following the post-translational cleavage of the N-terminal initiator methionine residue from the 147-amino-acid precursor. This mature chain has a calculated molecular weight of approximately 15,867 Da. The primary amino acid sequence of beta-globin begins with the N-terminal tripeptide Val-His-Leu (positions 1-3), which contributes to the formation of the oxygen-binding pocket in the assembled hemoglobin tetramer. The full sequence encodes a classic globin fold, featuring a high proportion of hydrophobic residues that facilitate heme interaction and overall stability. At the C-terminus, residue His-146 (position HC3) is a distinctive feature of beta-globin, playing a key role in pH-dependent proton binding that influences hemoglobin's functional properties; this histidine is absent in the shorter alpha-globin chain, which terminates at Arg-141 without an equivalent residue. In terms of secondary structure, beta-globin adopts eight alpha-helical segments, conventionally labeled A through H, which span approximately 75% of the polypeptide and are interconnected by short, non-helical loops (such as the AB, , EF, FG, and GH corners). These helices include key structural elements like the proximal (His-92 in F) that coordinates the iron, and the distal (His-63 in E) that stabilizes bound ligands. This helical architecture is conserved across family members but differs from alpha-globin, which lacks a D helix and thus has seven alpha-helices (A, B, C, E, F, G, H) due to its truncated length.

Tertiary Structure and Heme Binding

The beta-globin subunit adopts a compact globular tertiary structure known as the fold, characterized by eight alpha-helices (A through H) connected by non-helical loops, which enclose a hydrophobic core and form a crevice for the non-covalently bound . This fold, conserved across , positions the within a pocket primarily delineated by helices E and F, shielding the reactive iron center from the aqueous environment while allowing access. Hydrophobic residues such as leucines and valines (e.g., Val98 and Leu104) pack the core, providing through van der Waals interactions. The group, consisting of a ring with a central iron (Fe²⁺), is anchored in the pocket by coordination to the imidazole nitrogen of the proximal , His92 (position F8 on F), which lies on one side of the plane and tethers the to the protein. On the opposite (distal) side, His63 (position E7 on E) does not directly coordinate the iron but stabilizes bound dioxygen through a to its terminal oxygen atom, thereby enhancing affinity and discriminating against binding while preventing auto-oxidation to the ferric (Fe³⁺) state by excluding water molecules that could promote oxidation. Additional residues contribute to pocket integrity: Phe42 (CD1) contacts the heme edge via hydrophobic interactions, while Tyr145 (HC2) at the forms a with the distal , further securing the environment. Crystal structures reveal conformational shifts in the tertiary structure between the tense (T, deoxy) and relaxed (, oxy) states. In the T state (e.g., PDB ID: 1HGA), the iron atom is displaced ~0.4 Å out of the plane toward the proximal , distorting F and widening the ; upon oxygenation in the state, the iron moves into the plane, allowing F to straighten and the to narrow for tighter ligand binding. These changes, observed across high-resolution structures, underscore the subunit's adaptability without altering the overall fold.

Quaternary Assembly in Hemoglobin

The adult human (HbA) is a heterotetrameric protein composed of two α-globin and two β-globin subunits, forming an α₂β₂ that enables oxygen binding and transport. This assembly is essential for the protein's function, as isolated chains are prone to aggregation and precipitation due to exposed hydrophobic regions, whereas the tetrameric form buries these surfaces through subunit interactions, enhancing in the aqueous environment of erythrocytes. The tetramer has a molecular weight of approximately 64,500 Da, reflecting the combined masses of the polypeptide chains and four prosthetic groups. The quaternary structure features two distinct interfaces that stabilize the tetramer: the strong α₁β₁ intra-dimer contacts, which involve extensive hydrophobic and bonding interactions forming stable αβ dimers, and the weaker α₁β₂ inter-dimer contacts, which are more dynamic and critical for allosteric transitions. These interfaces were first elucidated through by and colleagues, revealing the tetramer's architecture in both deoxy and oxy forms. In the tense (T) deoxy state, the tetramer adopts an asymmetric configuration with lower oxygen affinity, stabilized by specific salt bridges and bonds at the interfaces, such as the ionic interaction between Asp-β94 (in the FG corner of the β subunit) and His-α122 (at the of the α subunit). This network of bonds constrains the heme groups in a domed conformation, contributing to the overall stability of the deoxy form. Upon oxygenation, the tetramer shifts to the relaxed (R) state, characterized by higher symmetry and disrupted salt bridges, allowing the hemes to adopt a planar configuration for enhanced oxygen binding. The transition from T to R involves rotation and sliding of the αβ dimers relative to each other by about 15 degrees, primarily at the α₁β₂ interface, which Perutz described as the stereochemical basis for cooperativity. This quaternary rearrangement not only facilitates sequential oxygen binding but also maintains the tetramer's solubility under physiological conditions, preventing the denaturation observed in monomeric or dimeric forms.

Physiological Function

Oxygen Binding and Transport

The hemoglobin subunit beta, as part of the adult tetramer (HbA, α₂β₂), contributes to oxygen transport by binding one oxygen molecule per beta chain via the iron atom in its associated . Each of the two beta subunits in HbA thus enables the tetramer to carry up to four oxygen molecules, facilitating efficient delivery from the lungs to peripheral tissues. In the pulmonary capillaries, where of oxygen (pO₂) is high (approximately 100 mmHg), oxygen binds readily to the iron in the beta subunits, achieving near-full saturation of HbA. As reaches systemic tissues with lower pO₂ (around 40 mmHg or less), oxygen is unloaded, with the p50 value—the pO₂ at which HbA is 50% saturated—being approximately 27 mmHg under standard conditions ( 7.4, 37°C). Beta-specific residues, such as at position 146 (His146β), play a key role in enhancing this tissue delivery by contributing to the , where decreased in active tissues stabilizes the deoxygenated state and promotes oxygen release. Compared to , a monomeric oxygen-storage protein in muscle, HbA exhibits lower oxygen affinity due to its tetrameric , which allows for physiological tuning of binding and release; myoglobin's higher affinity (p50 ~2-3 mmHg) suits storage, while HbA's design optimizes circulatory . In human blood, hemoglobin concentration averages about 15 g/dL, enabling an oxygen-carrying capacity of roughly 1.34 mL O₂ per gram of hemoglobin when fully saturated, sufficient to meet basal metabolic demands across tissues.

Allosteric Properties and Cooperativity

Hemoglobin exhibits cooperative oxygen binding, characterized by a sigmoidal oxygen dissociation curve that facilitates efficient oxygen loading in the lungs and unloading in tissues. This cooperativity is quantified by the Hill coefficient, approximately 2.8 for human hemoglobin, indicating positive interactions between subunits where binding of oxygen to one group increases the affinity of the others. Two primary models explain this behavior: the , which posits subunit-by-subunit transitions with induced fit changes, and the concerted Monod-Wyman-Changeux (MWC) model, which describes a symmetric equilibrium between tense (T, low-affinity) and relaxed (R, high-affinity) states of the entire tetramer, with oxygen binding shifting the equilibrium toward the R state. The MWC model is particularly well-suited to hemoglobin's allostery, as structural studies confirm global quaternary shifts upon oxygenation. Allosteric effectors modulate this by stabilizing the T state. 2,3-Bisphosphoglycerate (2,3-BPG) binds in the central cavity between the β subunits of deoxyhemoglobin, forming s with positively charged residues including β His-2 (NA2) and β Lys-82 (EF6), thereby reducing oxygen affinity and promoting unloading at tissues. The , a pH-dependent decrease in oxygen affinity, is largely mediated by the β subunit's C-terminal His-146 (HC3), whose side chain forms a with Asp-94 (FG1) in the T state; upon oxygenation and transition to the R state, this proton is released, accounting for about 40-50% of the alkaline Bohr protons. The (S) as a function of of oxygen (pO₂) is described by the Hill equation: S=pO2nP50n+pO2nS = \frac{pO_2^n}{P_{50}^n + pO_2^n} where n is the Hill coefficient (≈2.8) and P₅₀ is the pO₂ at 50% saturation. and CO₂ further influence oxygen affinity to optimize delivery under physiological conditions. Hemoglobin oxygenation is exothermic, so increased reduces affinity, enhancing oxygen release in warmer peripheral tissues. CO₂ lowers affinity both directly, by carbamylation of N-terminal amino groups on the β chains, and indirectly via acidification that amplifies the , facilitating unloading in metabolically active, CO₂-rich environments. The tetrameric assembly of , including the β subunits, is essential for these regulatory mechanisms.

Genetics and Biosynthesis

Gene Organization and Locus

The HBB gene, which encodes the beta-globin subunit of , is located on the short arm of at the cytogenetic band 11p15.4. It resides within the beta-globin gene cluster, a genomic region spanning approximately 50 kb that includes several related genes arranged in a 5' to 3' developmental order: (HBE1), gamma-G (HBG2), gamma-A (HBG1), delta (HBD), and beta (HBB). This cluster organization reflects the sequential expression of beta-like globins during human , from embryonic to adult stages, with HBB being the primary gene active in adult . The HBB gene itself spans about 1.6 kb of genomic DNA and consists of three exons interrupted by two introns, a structure conserved across vertebrate globin genes. Exon 1 encompasses the 5' untranslated region (UTR) and the coding sequence for the N-terminal portion, corresponding to helices A and B of the beta-globin protein (approximately amino acids 1-30). Exon 2 encodes the central region, including helices C, D, and E (amino acids 31-104), while exon 3 covers the C-terminal portion with helices F, G, and H, plus the 3' UTR (amino acids 105-146). The introns, particularly the larger second intron, contain non-coding elements that contribute to the overall gene architecture but are not translated. This split structure facilitates post-transcriptional processing and is typical of eukaryotic genes involved in protein synthesis. The proximal promoter of HBB features canonical elements including a located about 30 bp upstream of the transcription start site, which serves as a for the (TBP) and the general transcription factor TFIID, and a CCAAT box further upstream that recruits such as CP1/NF-Y. Unlike many genes, the HBB promoter lacks a CpG island, instead residing in an A+T-rich genomic context that influences its tissue-specific expression in erythroid cells. Nearby, within the beta-globin cluster, lies a non-functional beta-like (HBBP1, also known as ψβ1), positioned between the gamma and delta genes; this shares with HBB but harbors inactivating mutations that prevent its transcription and translation.

Transcriptional Regulation and Expression

The transcriptional regulation of the hemoglobin subunit beta (HBB) gene is primarily orchestrated by the locus control (LCR), a powerful enhancer element located approximately 10-60 kb upstream of the beta-like on 11p15.4. This LCR comprises five DNase I hypersensitive sites (HS1 through HS5), each spanning 200-400 bp and separated by , which collectively ensure high-level, erythroid-specific expression of HBB by maintaining an open conformation and promoting long-range interactions with the promoter via DNA looping mechanisms. In erythroid cells, the LCR recruits transcription factors and complexes to facilitate polymerase II loading and transcriptional elongation, thereby preventing silencing and position effects in transgenic models. Key erythroid transcription factors, including and EKLF (also known as KLF1), bind directly to the HBB proximal promoter to activate transcription. , a zinc-finger protein essential for erythroid differentiation, recognizes and binds WGATAR motifs approximately 50-100 bp upstream of the transcription start site, where it recruits coactivators to initiate HBB expression while repressing embryonic genes through context-dependent interactions with corepressors like FOG1 and NuRD. EKLF binds the conserved CACCC box at position -90 relative to the start site, driving adult-stage HBB activation by synergizing with the LCR and promoting histone acetylation at HS3; its absence leads to reduced beta-globin output and persistence of fetal gamma-globin. These factors operate in a combinatorial manner, with their levels increasing during definitive to fine-tune HBB activation. HBB expression follows a precise developmental timeline, remaining low during the embryonic stage when epsilon-globin predominates in yolk sac-derived primitive erythrocytes, before initiating around 6-8 weeks of as definitive shifts to the fetal liver. The transition from fetal gamma-globin to adult beta-globin begins with low-level HBB transcription at this early gestational point, but gamma-globin remains dominant (forming ~90% of non-alpha chains) until late , with the full switch completing perinatally as beta-globin synthesis surges and gamma expression is repressed by factors like BCL11A under EKLF influence. In adults, HBB peaks in reticulocytes, where it constitutes the majority of transcripts, supporting the assembly of (α₂β₂), which comprises 95-98% of total circulating . Post-transcriptionally, HBB mRNA exhibits high stability due to structured 3' elements that protect against degradation, indirectly modulated by iron availability through heme-mediated control rather than direct iron-response elements.

Protein Interactions

Dimer Formation with Alpha-Globin

The stable αβ dimer in is formed through extensive non-covalent interactions at the α₁β₁ (and symmetrically α₂β₂) interface, involving approximately 35 residues primarily from the B, G, and H helices of each subunit. These contacts include a mix of hydrophobic and polar interactions that ensure tight association. Key hydrophobic interactions are exemplified by the packing of β Phe36 (position B14) against α Leu91 (position FG8), contributing to the burial of nonpolar surfaces that drive dimerization. Polar interactions, such as the between β Asp94 (position FG1) and α Tyr42 (position C7), further stabilize the interface through electrostatic complementarity. The αβ dimer exhibits high stability, with a dissociation equilibrium constant (K_d) of approximately 10^{-12} M under physiological conditions, reflecting the strong affinity between unlike subunits that prevents rapid dissociation. This stability is crucial for maintaining balanced chain during ; imbalances, as seen in β-thalassemia where excess α chains precipitate due to lack of β partners, highlight the dimer's role in averting toxic aggregation of free monomers. Functionally, the αβ dimer serves as the fundamental building block for tetramer assembly, with two such dimers associating via weaker α₁β₂ contacts to form the complete tetramer. The dimer interface also initiates heme-heme communication, as subtle conformational changes propagated through these contacts contribute to the allosteric observed in oxygen binding. Structural studies using and (NMR) spectroscopy have elucidated the dimer interface, revealing its conservation across vertebrate species, which underscores evolutionary pressures to preserve hemoglobin's assembly and function. Seminal work at 5.5 resolution identified the core interface architecture, while higher-resolution analyses and NMR dynamics confirm the rigidity and residue-specific contacts essential for stability.

Interactions with Regulatory Proteins

The hemoglobin subunit beta (HBB) interacts with several non-globin regulatory proteins that modulate its stability, function, and integration into the erythrocyte proteome. One key chaperone is heat shock protein 90 (Hsp90), which binds to immature, heme-free forms of HBB to facilitate heme insertion and prevent aggregation during erythropoiesis. This ATP-dependent process ensures proper maturation of HBB in erythroid cells, reducing oxidative stress from unpaired or unstable globin chains. Unlike alpha-globin, which has a dedicated stabilizer, HBB relies on more general chaperones like Hsp90 for folding and stability in the absence of its dimer partner. In mature red blood cells, HBB within the tetramer associates with and cytosolic proteins to regulate physiological functions. The band 3 anion exchanger (SLC4A1), a major component of the erythrocyte , binds preferentially to deoxygenated , stabilizing the tense (T) state and influencing oxygen affinity through allosteric effects. This interaction, mediated by the cytoplasmic domain of band 3, also anchors to the , aiding in CO2 transport and membrane integrity. Similarly, I (CA1), abundant in erythrocytes, functionally couples with by catalyzing the reversible hydration of CO2 to ; the released protons are buffered by hemoglobin's beta subunits, enhancing the for efficient . Pathological variants of HBB, such as in (HbS), exhibit aberrant interactions that contribute to cellular damage. Deoxygenated HbS polymers bind abnormally to spectrin, the primary cytoskeletal protein, leading to membrane rigidity, oxidative injury, and . This disrupted binding destabilizes the spectrin-actin network, exacerbating erythrocyte deformation under low oxygen conditions. Proteomic databases highlight HBB's broader regulatory network in the erythroid context. According to the database, HBB has approximately 10 high-confidence interactors beyond globin subunits, including SLC4A1 (band 3), (carbonic anhydrase), SPTA1 and SPTB (alpha and beta spectrin), AHSP (though primarily alpha-specific, with co-expression), and ANK1 (ankyrin-1), all involved in stability, transport, and cytoskeletal anchoring with scores above 0.7. BioGRID corroborates these, listing over 200 interactions but emphasizing ~15 high-quality ones in erythrocyte , such as with chaperones and membrane effectors. These associations underscore HBB's role in a dynamic interactome that fine-tunes oxygen delivery and cell survival.

Clinical Significance

Beta-Thalassemia

Beta-thalassemia is an autosomal recessive disorder caused by mutations in the HBB gene that lead to reduced (β⁺) or absent (β⁰) synthesis of the β-globin chain, resulting in imbalanced globin production and hemolytic anemia. Inheritance requires two mutated alleles, one from each parent, with carriers (heterozygotes) typically asymptomatic or exhibiting mild microcytic anemia. Over 300 distinct mutations in the HBB gene have been identified, including point mutations, deletions, and insertions that affect transcription, RNA processing, or translation; common examples include the IVS1-5(G→C) splice site mutation prevalent in Mediterranean populations, which disrupts normal splicing and causes β⁰-thalassemia, and the promoter -101(C→T) variant, which reduces transcription efficiency leading to β⁺-thalassemia. The stems from the excess α-globin chains relative to β-globin, causing α-chain precipitation in erythroid precursors and mature erythrocytes, which damages cell membranes and triggers in the . This imbalance promotes ineffective , characterized by expanded but dysfunctional erythroid proliferation, and peripheral due to the fragility of circulating red blood cells, ultimately leading to chronic anemia and from repeated transfusions or increased intestinal absorption. Clinically, beta-thalassemia manifests in three main forms based on mutation severity and genotype: thalassemia major (homozygous β⁰ or compound heterozygous β⁰/β⁺), which presents with severe transfusion-dependent anemia by age 2, growth retardation, and splenomegaly; thalassemia intermedia (often β⁺/β⁺ or β⁺/β⁰ with modifiers), featuring moderate anemia that may not require lifelong transfusions but can cause complications like bone deformities; and thalassemia minor (heterozygous), a carrier state with mild or no symptoms. Treatments include chronic blood transfusions and iron chelation for major forms, hydroxyurea to stimulate fetal hemoglobin production and reduce transfusion needs in select intermedia cases, and gene therapies such as betibeglogene autotemcel (Zynteglo), approved by the FDA in 2022, and exagamglogene autotemcel (Casgevy), approved by the FDA in 2024, for transfusion-dependent patients aged 12 and older; both involve autologous hematopoietic stem cell modification—Zynteglo via lentiviral transduction with a functional β-globin vector and Casgevy via CRISPR-based editing to reactivate fetal hemoglobin production.

Sickle Cell Disease

Sickle cell disease (SCD) is caused by a homozygous missense mutation in the HBB gene, substituting glutamic acid for valine at the sixth position of the beta-globin chain (β6 Glu→Val, rs334), resulting in the production of hemoglobin S (HbS). This mutation creates a hydrophobic patch on the surface of the deoxy form of HbS, which promotes the polymerization of hemoglobin molecules into rigid fibers under low-oxygen conditions. The formation of these fibers distorts red blood cells (RBCs) into a sickle shape, leading to vaso-occlusion, chronic hemolysis, and repeated episodes of pain and organ damage. Globally, SCD affects approximately 500,000 infants born each year, with the highest burden in , where over 75% of cases occur. The persistence of the HbS in these populations is largely due to a , where individuals with one copy of the mutation (HbAS) exhibit 40–90% protection against severe caused by Plasmodium falciparum, balancing the disease risk in homozygous individuals (HbSS). Current treatments include , approved by the FDA in 2019, which acts as an allosteric modifier to increase the oxygen affinity of HbS, thereby reducing polymerization and improving hemoglobin levels. Additionally, gene therapies, including CRISPR-based exagamglogene autotemcel (Casgevy) and lentiviral vector-based lovotibeglogene autotemcel (Lyfgenia), both received FDA approval in 2023 following successful phase 3 trials, enabling modification of hematopoietic stem cells to reactivate production or add functional beta-globin, offering potential long-term remission for eligible patients.

Other Variant Hemoglobinopathies

Hemoglobin C (HbC), resulting from a β6 (A3) Glu→Lys substitution in the HBB gene, is a common variant primarily found in individuals of West African descent. In heterozygous carriers, it is typically asymptomatic, but homozygotes or compound heterozygotes with HbA develop mild characterized by and the formation of intracellular crystals in red blood cells, leading to reduced erythrocyte deformability. This variant also confers partial resistance to severe malaria, similar to other β-globin mutations, contributing to its persistence in malaria-endemic regions. Hemoglobin E (HbE), caused by a β26 (B8) Glu→Lys , represents the most prevalent structural hemoglobin variant worldwide, with carrier frequencies reaching 30% in parts of , such as northeastern , and up to 50-70% in the "hemoglobin E triangle" encompassing , , and . Heterozygotes exhibit minimal clinical effects, often limited to mild , but with β-thalassemia results in a intermedia-like with moderate to severe , ineffective , and potential transfusion dependence. The introduces a cryptic splice site, reducing βE-globin synthesis to about 20-30% of normal levels, which exacerbates the in combinations. Unstable hemoglobin variants arise from HBB mutations that disrupt the β-globin's heme-binding pocket or overall folding, leading to protein precipitation and . A prototypical example is Hb Köln, due to a β98 (FG5) Val→Met substitution, which destabilizes the group and promotes oxidative damage, resulting in formation—denatured hemoglobin precipitates—and chronic extravascular hemolysis often requiring in severe cases. These variants typically present in childhood with , gallstones, and variable severity, depending on the degree of instability. Rare HBB variants include the hemoglobin M (HbM) diseases, which cause congenital through mutations stabilizing the ferric (Fe³⁺) iron state, impairing oxygen transport and leading to without significant . For instance, Hb M Hyde Park [β92 (F8) His→Tyr] disrupts the proximal histidine's coordination with iron, elevating levels to 20-30% and resulting in lifelong asymptomatic or mildly symptomatic treatable with in acute exacerbations. The HbVar database, a comprehensive locus-specific resource, catalogs over 1,800 hemoglobin variants and mutations, including more than 900 in the HBB gene, highlighting the diversity of these pathological alterations.

Evolutionary Aspects

Human-Specific Adaptations

The hemoglobin subunit beta (HBB) gene has undergone human-specific adaptations primarily driven by selective pressures from () in endemic regions, resulting in variants that confer heterozygote advantages against severe disease while imposing costs in homozygotes. These adaptations highlight balanced polymorphisms where heterozygous carriers experience reduced mortality, offsetting the risk of hemoglobinopathies in homozygous states. Key examples include the sickle cell allele (HbS), (HbC), (HbE), and beta-thalassemia alleles, which emerged and spread in and during periods of intense malarial exposure. The (β6 Glu→Val) originated from a single event approximately 7,300 years ago in central-west , near present-day , during the mid-Holocene wet phase that expanded suitable habitats for vectors. This variant rapidly increased in frequency due to strong positive selection from malaria resistance in heterozygotes (HbAS), who exhibit up to 90% protection against severe falciparum malaria through mechanisms such as impaired parasite growth in sickle-prone erythrocytes and enhanced immune clearance. In West African populations historically exposed to high malaria prevalence, HbS frequencies reached 10-20%, with carrier rates up to 25-30% in regions like and , reflecting the intensity of selection. Similarly, the HbC allele (β6 Glu→Lys), prevalent in , provides comparable malaria protection in heterozygotes by altering properties that hinder parasite invasion and cytoadherence, reducing severe outcomes by about 30-50%. Though its exact age is less precisely dated, HbC likely arose more recently than HbS, with high frequencies (>20%) in areas like and northern , where it co-occurs with HbS under shared selective pressures. In , the HbE allele (β26 Glu→Lys) emerged around 5,000 years ago, offering resistance to severe via reduced expression and microcytic erythrocytes that limit parasite proliferation, with allele frequencies exceeding 50% in parts of and . Beta-thalassemia alleles, which reduce or abolish β-globin production, also demonstrate heterozygote advantages, causing mild but conferring 50-80% protection against severe through on intraerythrocytic parasites and enhanced of infected cells. These mutations, diverse across Mediterranean, African, and Asian populations, maintain frequencies of 5-15% in malarial zones due to this balancing selection, as first hypothesized by Haldane in 1949. In modern contexts, these HBB variants have spread globally through human migrations, such as the African diaspora during the transatlantic slave trade, which distributed HbS to the Americas and Europe, altering local allele frequencies and increasing compound heterozygote risks like HbSC disease. With effective malaria control and eradication efforts reducing global malaria incidence by 27% and mortality by 63% since 2000, however, progress has stalled since 2015 with a slight increase in incidence rates as of 2023, the selective advantage of these alleles is diminishing, potentially leading to gradual declines in frequency over generations as the homozygous disadvantages (e.g., sickle cell disease, thalassemia major) persist without offsetting benefits.

Evolution Within the Globin Gene Family

The globin superfamily traces its origins to ancient prokaryotic proteins that emerged approximately 3 billion years ago, shortly after the advent of life on , primarily functioning in (NO) detoxification rather than oxygen transport. These early globin-like molecules, such as bacterial flavohemoglobins, protected cells from the toxic effects of NO produced by or environmental sources. Oxygen-binding capabilities evolved later, likely following the around 2.4 billion years ago, when atmospheric oxygen levels rose sufficiently to favor the adaptation of globins for reversible O2 binding and transport in aerobic organisms. In vertebrates, the modern hemoglobin structure arose through a series of gene duplications within the globin family. An ancestral single-copy globin gene underwent tandem duplication approximately 450–500 million years ago (mya), giving rise to the proto-alpha and proto-beta globin lineages that segregated into distinct chromosomal clusters. The beta-globin cluster specifically emerged around 450 mya, prior to the divergence of cartilaginous fishes from other vertebrates, enabling the formation of heterotetrameric s with cooperative oxygen binding. These duplications facilitated functional diversification, with beta-like genes adapting for adult hemoglobin expression in higher vertebrates. In mammals, further refinements occurred within the beta-globin cluster, including a tandem duplication event that produced the HBB (beta) and HBD (delta) genes more than 40 mya in the stem lineage of placental mammals. While remains the primary functional for adult , HBD expresses at low levels, and associated pseudogenes (such as the human ψβ1) exhibit patterns of substitution consistent with neutral , lacking selective pressure due to their non-functional status. Sequence conservation across mammals is high, with the sharing approximately 80% identity with the ortholog Hbb-b1, reflecting strong purifying selection to maintain oxygen transport efficacy. However, sites associated with resistance, such as those underlying the sickle cell mutation (HbS), show signatures of positive selection in populations exposed to .

References

  1. https://www.ncbi.nlm.nih.gov/gene/3043
  2. https://medlineplus.gov/genetics/gene/hbb/
  3. https://www.ncbi.nlm.nih.gov/omim/141900
  4. https://pmc.ncbi.nlm.nih.gov/articles/PMC7370311/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC3165113/
  6. https://www.uniprot.org/uniprotkb/P68871/entry
  7. https://pubmed.ncbi.nlm.nih.gov/6693406/
  8. https://www.sciencedirect.com/topics/medicine-and-dentistry/hemoglobin-alpha-chain
  9. https://themedicalbiochemistrypage.org/hemoglobin-and-myoglobin/
  10. https://www.rcsb.org/structure/1HGA
  11. https://pubmed.ncbi.nlm.nih.gov/3476938/
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC9043147/
  13. https://www.ncbi.nlm.nih.gov/books/NBK538336/
  14. https://www.ncbi.nlm.nih.gov/books/NBK54103/
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC7547706/
  16. https://www.researchgate.net/publication/16503738_Involvement_of_His_HC3_146_beta_in_the_Bohr_effect_of_human_hemoglobin_Studies_of_native_and_N-ethylmaleimide-treated_hemoglobin_A_and_hemoglobin_Cowtown_beta_146_His_replaced_by_Leu
  17. https://www.ncbi.nlm.nih.gov/books/NBK544256/
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC8994510/
  19. https://www.pnas.org/doi/10.1073/pnas.69.2.335
  20. https://www.pnas.org/doi/10.1073/pnas.1413566111
  21. https://www.pnas.org/doi/10.1073/pnas.1205809109
  22. https://www.nature.com/articles/s41598-021-04112-y
  23. https://www.jbc.org/article/S0021-9258%2817%2943552-6/fulltext
  24. https://pmc.ncbi.nlm.nih.gov/articles/PMC3699289/
  25. https://www.cell.com/biophysj/fulltext/S0006-3495%2812%2904345-7
  26. https://www.nature.com/articles/s41598-020-73560-9
  27. https://www.nature.com/articles/2221243a0
  28. https://www.pnas.org/doi/10.1073/pnas.1011995108
  29. https://omim.org/entry/141900
  30. https://doi.org/10.1242/jeb.201.8.1099
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC2696286/
  32. https://pmc.ncbi.nlm.nih.gov/articles/PMC2897567/
  33. https://www.pnas.org/doi/10.1073/pnas.96.18.10051
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC3087525/
  35. https://emedicine.medscape.com/article/2085637-overview
  36. https://www.sciencedirect.com/science/article/pii/S0006497120612344
  37. https://pubmed.ncbi.nlm.nih.gov/5659637/
  38. https://www.researchgate.net/figure/Thermodynamic-parameters-for-monomer-dimer-and-dimer-tetramer-associations-of-human_tbl1_20738122
  39. https://pubmed.ncbi.nlm.nih.gov/833131/
  40. https://ashpublications.org/blood/article/69/1/1/165434/Subunit-assembly-of-hemoglobin-an-important
  41. https://pubmed.ncbi.nlm.nih.gov/15178680/
  42. https://pubmed.ncbi.nlm.nih.gov/29358373/
  43. https://www.pnas.org/doi/10.1073/pnas.1717993115
  44. https://pubmed.ncbi.nlm.nih.gov/6355641/
  45. https://www.sciencedirect.com/science/article/pii/S000527361630116X
  46. https://www.sciencedirect.com/science/article/abs/pii/S1079979603000196
  47. https://pubmed.ncbi.nlm.nih.gov/32053762/
  48. https://string-db.org/network/9606.ENSP00000494175
  49. https://thebiogrid.org/109293/summary/homo-sapiens/hbb.html
  50. https://www.ncbi.nlm.nih.gov/books/NBK1426/
  51. https://medlineplus.gov/genetics/condition/beta-thalassemia/
  52. https://www.tandfonline.com/doi/full/10.1080/17474086.2021.1860003
  53. https://pmc.ncbi.nlm.nih.gov/articles/PMC10147086/
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC3543079/
  55. https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.880752/full
  56. https://emedicine.medscape.com/article/206490-overview
  57. https://www.fda.gov/media/161472/download
  58. https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1480831/full
  59. https://www.fda.gov/news-events/press-announcements/fda-approves-casgevy-transfusion-dependent-beta-thalassemia
  60. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-fda-approval-zynteglor-first-gene-therapy
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC5696113/
  62. https://onlinelibrary.wiley.com/doi/10.1080/10739680490278312
  63. https://www.who.int/news-room/fact-sheets/detail/sickle-cell-disease
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC10872868/
  65. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-voxelotor-sickle-cell-disease
  66. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
  67. https://www.ncbi.nlm.nih.gov/books/NBK559043/
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC2553125/
  69. https://www.ncbi.nlm.nih.gov/clinvar/variation/15126/
  70. https://pmc.ncbi.nlm.nih.gov/articles/PMC6186250/
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC3426822/
  72. https://pmc.ncbi.nlm.nih.gov/articles/PMC5421591/
  73. https://www.ncbi.nlm.nih.gov/clinvar/variation/15241/
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC1484532/
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC7536569/
  76. https://pubmed.ncbi.nlm.nih.gov/31267164/
  77. https://www.archivesofmedicalscience.com/Identification-of-seven-novel-variants-in-the-globin-gene-in-transfusion-dependent%2C95285%2C0%2C2.html
  78. https://www.sciencedirect.com/science/article/pii/S000292971830048X
  79. https://www.pnas.org/doi/10.1073/pnas.1505665112
  80. https://www.nature.com/articles/ncomms1104
  81. https://pmc.ncbi.nlm.nih.gov/articles/PMC1182083/
  82. https://www.pnas.org/doi/10.1073/pnas.0910142106
  83. https://www.sciencedirect.com/science/article/pii/S014067361261229X
  84. https://www.who.int/news-room/fact-sheets/detail/malaria
  85. https://www.researchgate.net/publication/236092837_Bacterial_and_Archaeal_Globins_-_a_Revised_Perspective
  86. https://www.pnas.org/doi/10.1073/pnas.96.18.9967
  87. https://pmc.ncbi.nlm.nih.gov/articles/PMC2234189/
  88. https://www.pnas.org/doi/10.1073/pnas.1006756107
  89. https://www.sciencedirect.com/topics/medicine-and-dentistry/globin-gene
  90. https://www.nature.com/articles/292237a0
  91. https://pubmed.ncbi.nlm.nih.gov/16175509/
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