Structural bases of the inhibitory effects of hemoglobin F and hemoglobin A2 on the polymerization of hemoglobin S
Open accessAbstract
We have previously found that the inhibitory effect of hemoglobin F (Hb F) on the polymerization of Hb S proceeds via the formation of asymmetrical hybrid tetramers of the type alpha2betasgamma. Examination of the gelling properties of binary mixtures of Hb S and several Hb variants now shows that, among the gamma chain amino acid residues that differ from those of the beta chain, residues gamma80 (EF4) and gamma87 (F3) are at least partly responsible for this inhibition. Furthermore, we find that mixing Hb A2(alpha2delta2) with Hb S strongly inhibits gelling to an extent similar to that seen with Hb S/Hb F mixtures; this inhibition is attributable to amino acid differences between the delta and beta chain sequences at positions delta22 (B4) and delta87 (F3). Therefore, residues 22, 80, and 87 of the beta chain appear to be involved in intermolecular contact sites that stabilize the deoxy Hb S polymers.
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Nagel et al showed that the glutamine at position 87 in the g-globin chain was 1 of 2 residues accounting for the inhibitory effect of HbF on HbS polymerization.
“More than 40 years ago, Nagel et al 114 showed that the glutamine (Q) at position 87 in the g-globin chain was 1 of 2 residues accounting for the inhibitory effect of HbF on HbS polymerization.”
From Fetal hemoglobin in sickle cell anemia (2020) · cites this paper as [114]
The Results and Discussion identifies γ-chain residues 80 and 87 as contributing to HbF’s inhibition of HbS gelation, and Table 3 identifies residue 87 as glutamine. The paper says these sites are responsible *at least partially* and considers possible contributions from other residues, so it does not establish that exactly two residues account for the effect. (LLM, conf=0.86)
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- Authors
- Nagel, R. L., Bookchin, R. M., Johnson, J., Labie, D., Wajcman, H., Isaac-Sodeye, W. A., Honig, G. R., Schilirò, G., Crookston, J. H., & Matsutomo, K.
- Affiliations
- University of Nigeria (NG)
- ORCID
- Schilirò, G
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1979-02
- Volume
- 76
- Issue
- 2
- Pages
- 670-672
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC383012
- OpenAlex
- W1987037884
- Semantic Scholar
- 36a913eed7cc2fc283090def5f01e0c9429d8fc1
- Cited by
- 196
- References
- 12
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 5 · 2016: 9 · 2015: 7 · 2014: 5 · 2013: 4 · 2012: 6
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- hemoglobin S, fetal hemoglobin, hemoglobin A2, hemoglobin polymerization, sickle cell disease, delta chain, protein gelling, hemoglobin variants
- MeSH terms
- Amino Acid Sequence, Fetal Hemoglobin, Hemoglobin A, Hemoglobin A2, Hemoglobin, Sickle, Hemoglobins, Abnormal, Protein Binding, Structure-Activity Relationship, Macromolecular Substances
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