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Biophy J:使用光散射技术揭示镰刀状细胞病的发病机制

  1. Biophy J
  2. 光散射技术
  3. 发病机制
  4. 镰刀状细胞病

来源:生物谷 2013-11-07 00:05

2013年11月7日 讯 /生物谷BIOON/ --在镰刀形细胞病中,血红蛋白作为携带养分的结构,其可以形成使得红细胞变硬以及疾病恶化的纤维。近日,刊登在国际杂志Biophysical Journal上的一篇报告中,来自德雷塞尔大学的研究者通过使用光散射技术对血红蛋白形成纤维的过程进行了深入研究,相关研究或可帮助科学家开发干预此疾病发生过程的新型疗法。

2013年11月7日 讯 /生物谷BIOON/ --在镰刀形细胞病中,血红蛋白作为携带养分的结构,其可以形成使得红细胞变硬以及疾病恶化的纤维。近日,刊登在国际杂志Biophysical Journal上的一篇报告中,来自德雷塞尔大学的研究者通过使用光散射技术对血红蛋白形成纤维的过程进行了深入研究,相关研究或可帮助科学家开发干预此疾病发生过程的新型疗法。

红细胞就类似于小布袋一样,其包含有很多血红蛋白分子,其可以不停滑动维持细胞的湿润环境,但这并非易事,因为在分子表面存在有正负电荷,而且油性斑可以排斥水分子而提供天然的配偶体。

在镰刀形细胞病中,血红蛋白的突变会使得大量僵硬的纤维、或者聚合物将红细胞变得更加容易曲折。研究者Frank Ferrone与其同事表示,当温度过高或者血红蛋白溶液浓度过大,血红蛋白的确可以聚集在一起,当然这对于正常血红蛋白来说必不可少,但是对于镰刀状血红蛋白来说尤为明显;当在生理学条件下,镰刀形红细胞血红蛋白更易于被成对发现,而并不是以单一分子被发现。

研究者通过进行光散射技术得到了上述发现,通过将镰刀状血红蛋白的特性同正常血红蛋白的特性进行对比,研究者就可以确定镰刀聚合物结合的相对强度,这种结合方式将使得镰刀状血红蛋白变得和弹簧一样,这将有助于研究者理解其硬度从而揭示疾病的发生机制。

这项研究也为研究者开发新型靶向作用血红蛋白聚合体形成位点的药物疗法提供了很多思路和研究基础。(生物谷Bioon.com)

Dissecting the Energies that Stabilize Sickle Hemoglobin Polymers

Yihua Wang and Frank A. Ferrone,

Sickle hemoglobin forms long, multistranded polymers that account for the pathophysiology of the disease. The molecules in these polymers make significant contacts along the polymer axis (i.e., axial contacts) as well as making diagonally directed contacts (i.e., lateral contacts). The axial contacts do not engage the mutant β6 Val and its nonmutant receptor region on an adjacent molecule, in contrast to the lateral contacts which do involve the mutation site. We have studied the association process by elastic light scattering measurements as a function of temperature, concentration, and primary and quaternary structure, employing an instrument of our own construction. Even well below the solubility for polymer formation, we find a difference between the association behavior of deoxy sickle hemoglobin molecules (HbS), which can polymerize at higher concentration, in comparison to COHbS, COHbA, or deoxygenated Hemoglobin A (HbA), none of which have the capacity to form polymers. The nonpolymerizable species are all quite similar to one another, and show much less association than deoxy HbS. We conclude that axial contacts are significantly weaker than the lateral ones. All the associations are entropically favored, and enthalpically disfavored, typical of hydrophobic interactions. For nonpolymerizable Hemoglobin, Ho was 35 4 kcal/mol, and S was 102.7 0.5 cal/(molK). For deoxyHbS, Ho was 19 2 kcal/mol, and S was 56.9 0.5 cal/(molK). The results are quantitatively consistent with the thermodynamics of polymer assembly, suggesting that the dimer contacts and polymer contacts are very similar, and they explain a previously documented significant anisotropy between bending and torsional moduli. Unexpectedly, the results also imply that a substantial fraction of the hemoglobin has associated into dimeric species at physiological conditions.

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