Allosteric transitions in hemoglobin revisited

• Published in: Biochimica et biophysica acta. General subjects Vol. 1864; no. 2; p. 129335
• Main Author: Shibayama, Naoya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.02.2020
• Subjects: Allosteric regulation; Allostery; Conformational change; Hemoglobin; humans; ligands; oxygen; Protein function; structure-activity relationships; X-ray crystallography; XL[α(Fe)β(Ni)]2; HL; nmax; FL; Conformational change; PDB; X-ray crystallography; IHP; R; XL[α(Ni)β(Fe)]2; T; Protein function; Hemoglobin; Pi; R2; Allostery; RMSD; P50; BZF; XL[α(Fe-CO)β(Ni)][α(Ni)β(Fe-CO)]; XL[α(Fe)β(Ni)][α(Ni)β(Fe)]; RR2; PEG; Allosteric regulation; BPG; XL[α(Fe)β(Fe)][α(Ni)β(Ni)]; TR; Ki
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2019.03.021

Human hemoglobin is an allosteric protein that exerts exquisite control over ligand binding through large-scale conformational changes. The two-state model without intermediates offers a simple qualitative description of the allosteric behavior of hemoglobin, as presented in textbooks. However, there is renewed interest in this topic due to recent experimental breakthroughs that show how hemoglobin actually undergoes conformational transitions in response to environmental changes. I review the current understanding of hemoglobin structure-function relationships revealed by recent discoveries. A unique single crystal, in which three protein molecules are allowed to express a whole range of quaternary structures, helped to reveal the detailed transition pathway including various intermediate forms. I also discuss the potential of single-molecule techniques that are currently under examination. New crystallographic approaches reveal that the hemoglobin allosteric transition involves population shifts in multiple quaternary conformers rather than a simple two-state switch, and that coexisting individual conformers may have disproportionate effects on the apparent O2 affinity of hemoglobin. These approaches provide a further level of complexity on the textbook statement of hemoglobin allostery, highlighting the relevance of conformational distributions in controlling the function and regulation of allosteric proteins. •Despite much effort, structural basis for hemoglobin allostery has been controversial.•A unique single crystal can reveal the full allosteric pathway in hemoglobin.•Results clarify equilibria of multiple conformations including a third affinity state.•Conformational population shifts are critical to hemoglobin allostery.•Conformational population shifts are consistent with the concerted MWC model.