E DIFFS AT SUBUNIT INTERFACES OF HUMAN HBS CORRELATE WITH THEIR DEV PROFILE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 描述了在蛋白质组装过程中发生的正常人类血红蛋白的一个以前未被认识的功能，即亚基配对及其持续时间的自我调节，其产生于亚基相互作用的不同强度。虽然已知许多突变的人类血红蛋白改变了亚单位界面强度，但正常的胚胎、胎儿和成人血红蛋白的亚基界面强度并没有显著不同。然而，在对八种正常氧合人类血红蛋白中的七种亚基界面的综合研究中，我们发现与以前的报道相反，四聚体-二聚体界面的强度，即四聚体-二聚体界面的自由能，与以前的报道相反，差异3个数量级，并显示出类似于各种珠蛋白亚基类型随时间变化的起伏曲线。二聚体界面强度也是可变的，并与其发育状况呈线性相关。胚胎血红蛋白最弱；胎儿血红蛋白中等强度，成人血红蛋白最强。这种模式还与它们不同的O(2)亲和力和对变构调节分子的反应有关。胎儿血红蛋白的乙酰化减弱了其异常强烈的亚基相互作用，并随着其表达水平的降低和成人血红蛋白A的形成而逐渐发生；提出了一种因果关系。由于界面强度的差异，珠蛋白基因序列和亚基之间的竞争的相对贡献被发现是互补的，并在遗传学、热力学和发育之间建立了联系。这项工作已经出版：(36.Manning LR，Russell Je，Popowicz AM，Manning RS，Padovan JC，Manning JM。正常人血红蛋白亚基界面上的能量差异与其发育特征有关。生物化学。2009年8月18日；48(32)：7568-74。)

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A previously unrecognized function of normal human hemoglobins occurring during protein assembly is described, i.e. self-regulation of subunit pairings and their durations arising from the variable strengths of their subunit interactions. Although many mutant human hemoglobins are known to have altered subunit interface strengths, those of the normal embryonic, fetal, and adult human hemoglobins have not been considered to differ significantly. However, in a comprehensive study of both types of subunit interfaces of seven of the eight normal oxy human hemoglobins, we found that the strengths, i.e., the free energies of the tetramer-dimer interfaces, contrary to previous reports, differ by 3 orders of magnitude and display an undulating profile similar to the transitions ("switches") of various globin subunit types over time. The dimer interface strengths are also variable and correlate linearly with their developmental profile. Embryonic hemoglobins are the weakest; fetal hemoglobin is of intermediate strength, and adult hemoglobins are the strongest. The pattern also correlates generally with their different O(2) affinities and responses to allosteric regulatory molecules. Acetylation of fetal hemoglobin weakens its unusually strong subunit interactions and occurs progressively as its level of expression diminishes and adult hemoglobin A formation begins; a causal relationship is suggested. The relative contributions of globin gene order and competition among subunits due to differences in their interface strengths were found to be complementary and establish a connection among genetics, thermodynamics, and development. This work has been published: (36. Manning LR, Russell JE, Popowicz AM, Manning RS, Padovan JC, Manning JM. Energetic differences at the subunit interfaces of normal human hemoglobins correlate with their developmental profile. Biochemistry. 2009 Aug 18;48(32):7568-74.)