Manning James M, Manning Lois R, Dumoulin Antoine, Padovan Julio C, Chait Brian
Department of Biology, Northeastern University, Boston, MA, 02115, USA.
Department of Developability, Pierre Fabre Research Centre, Castres, 81106, France.
Subcell Biochem. 2020;94:275-296. doi: 10.1007/978-3-030-41769-7_11.
During the past two decades, significant advances have been made in our understanding of the human fetal and embryonic hemoglobins made possible by the availability of pure, highly characterized materials and novel methods, e.g., nano gel filtration, to study their properties and to correct some misconceptions. For example, whereas the structures of the human adult, fetal, and embryonic hemoglobins are very similar, it has generally been assumed that functional differences between them are due to primary sequence effects. However, more recent studies indicate that the strengths of the interactions between their subunits are very different leading to changes in their oxygen binding properties compared to adult hemoglobin. Fetal hemoglobin in the oxy conformation is a much stronger tetramer than adult hemoglobin and dissociates to dimers 70-times less than adult hemoglobin. This property may form the basis for its protective effect against malaria. A major source of the increased strength of fetal hemoglobin resides within the A-helix of its gamma subunit as demonstrated in studies with the hybrid hemoglobin Felix and related hybrids. Re-activating fetal hemoglobin synthesis in vivo is currently a major focus of clinical efforts designed to treat sickle cell anemia since it inhibits the aggregation of sickle hemoglobin. The mechanisms for both the increased oxygen affinity of fetal hemoglobin and its decreased response to DPG have been clarified. Acetylated fetal hemoglobin, which makes up 10-20% of total fetal hemoglobin, has a significantly weakened tetramer structure suggesting a similar role for other kinds of protein acetylation. Embryonic hemoglobins have the weakest tetramer and dimer structures. In general, the progressively increasing strength of the subunit interfaces of the hemoglobin family during development from the embryonic to the fetal and ultimately to the adult types correlates with their temporal appearance and disappearance in vivo, i.e., ontogeny.
在过去二十年里，随着纯的、高度特征化的材料以及纳米凝胶过滤等新方法的出现，我们对人类胎儿和胚胎血红蛋白的认识取得了重大进展，这些材料和方法使我们能够研究它们的特性并纠正一些误解。例如，尽管人类成人、胎儿和胚胎血红蛋白的结构非常相似，但人们通常认为它们之间的功能差异是由一级序列效应导致的。然而，最近的研究表明，它们亚基之间相互作用的强度差异很大，与成人血红蛋白相比，这导致了它们氧结合特性的变化。处于氧合构象的胎儿血红蛋白是一种比成人血红蛋白更强的四聚体，其解离成二聚体的程度比成人血红蛋白少70倍。这一特性可能构成其抗疟疾保护作用的基础。胎儿血红蛋白强度增加的一个主要来源在于其γ亚基的A螺旋，这在对杂交血红蛋白Felix及相关杂种的研究中得到了证实。在体内重新激活胎儿血红蛋白的合成目前是旨在治疗镰状细胞贫血的临床努力的一个主要重点，因为它能抑制镰状血红蛋白的聚集。胎儿血红蛋白氧亲和力增加及其对DPG反应降低的机制已经阐明。占胎儿血红蛋白总量10 - 20%的乙酰化胎儿血红蛋白具有明显减弱的四聚体结构，这表明其他类型的蛋白质乙酰化可能也有类似作用。胚胎血红蛋白具有最弱的四聚体和二聚体结构。一般来说，从胚胎型到胎儿型再到最终成人型的血红蛋白家族在发育过程中亚基界面强度的逐渐增加与其在体内的出现和消失时间，即个体发生，相关。
