Hemoglobin subunit beta

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HBB
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"HBB" redirects here. For other uses, see HBB (disambiguation).
HBB
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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
chromosome 11
at position p15.5.

Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a

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.

HBB is encoded by the HBB gene on

genetic resistance to malaria.[6][7] At least 50 disease-causing mutations in this gene have been discovered.[8]

Gene locus

Main article: Human β-globin locus

HBB protein is produced by the gene HBB which is located in the multigene locus of

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

HBB

interacts with Haemoglobin, alpha 1 (HBA1) to form haemoglobin A, the major haemoglobin in adult humans.[10][11] 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 haemoglobin.[12]

Associated genetic disorders

Beta thalassemia

bone marrow transplantation.[14][15]

According to a recent study, the stop gain mutation Gln40stop in HBB gene is a common cause of

LDL levels in carriers, so the authors suggest that is due to the need of cholesterol to regenerate cell membranes.[16]

Sickle cell disease

More than a thousand naturally occurring HBB variants have been discovered. The most common is HbS, which causes

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

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

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

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 Africa where malaria is epidemic.[26] 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.[6][27] Such selection markers are important for tracing human ancestry and diversification from Africa.[28]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000244734 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000073940 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b "Entrez Gene: HBB hemoglobin, beta".
  6. ^ a b Sabeti PC (2008). "Natural selection: uncovering mechanisms of evolutionary adaptation to infectious disease". Nature Education. 1 (1): 13.
  7. ^
    PMID 16001361
    .
  8. PMID 31819097
    .
  9. PMID 11895428
    .
  10. S2CID 8235923
    .
  11. PMID 6644819
    .
  12. ^ "Hemoglobin Synthesis". harvard.edu. Harvard University. 2002. Retrieved 18 November 2014.
  13. ^ H. Franklin Bunn, Vijay G. Sankaran (2017). "8". Pathology of blood disorders. pp. 927–933.
  14. PMID 19678601
    .
  15. ^ "Beta thalassemia". Genetics Home Reference. U.S. National Library of Medicine. 11 November 2014. Retrieved 18 November 2014.
  16. PMID 26366554
    .
  17. PMID 23388674
    .
  18. S2CID 1541253
    .
  19. PMID 23170194
    .
  20. PMID 23591685
    .
  21. S2CID 4360808
    .
  22. PMID 18689228
    .
  23. PMID 22089616
    .
  24. PMID 12149194
    .
  25. S2CID 23734166
    .
  26. S2CID 7801737
    .
  27. PMID 12433581
    .
  28. PMID 17056248
    .

Further reading

External links
Wikimedia Commons has media related to Hemoglobin, beta-chain.
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