Hemoglobin subunit beta (Sickle variant) (HbS)

Sickle hemoglobin (HbS) is a pathological variant of the hemoglobin protein caused by a single amino acid substitution (Glu6Val) in the beta-globin chain (HBB) [1, 4]. This mutation creates a hydrophobic patch on the beta-chain interface that is exposed when the protein is in its deoxygenated state [3, 5]. These patches facilitate the polymerization of HbS tetramers into long, rigid fibers, which distort red blood cells into a characteristic sickle shape [3, 5]. The resulting sickled cells lead to vaso-occlusive crises, chronic hemolytic anemia, and widespread organ damage [2, 5]. The beta-chain interface is the primary site of this polymerization, making it a critical target for therapeutic intervention [3]. Drugs such as Voxelotor act as allosteric modulators that bind to the hemoglobin tetramer and increase its affinity for oxygen [2]. By stabilizing the oxygenated (R-state) conformation, these therapies prevent the exposure of the hydrophobic interface, thereby inhibiting polymerization and improving red blood cell health [2, 3].

Other names

Sickle hemoglobinHemoglobin SHBB Glu6Val mutationSickle cell hemoglobinHemoglobin subunit beta interface

Allosteric modulation of hemoglobin to increase oxygen affinity, thereby stabilizing the oxygenated (R-state) conformation and preventing the deoxygenation-induced polymerization of sickle hemoglobin at the beta-chain interface [2, 3].