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An ATP-dependent mechanism protects spectrin against glycation in human erythrocytes

ATP 依赖性机制可保护血影蛋白免受人红细胞糖化的影响

基本信息

批准号：
19590289
负责人：
MANNO Sumie
金额：
$ 2.91万
依托单位：
Tokyo Women's Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2007
资助国家：
日本
起止时间：
2007 至 2009
项目状态：
已结题

项目摘要

Human erythrocytes are continuously exposed to glucose which reacts with the amino terminus of the ・-chain of hemoglobin (Hb) to form glycated Hb, HbA1c, levels of which increase with the age of the circulating cell. In contrast to extensive insights into glycation of hemoglobin, little is known about glycation of erythrocyte membrane proteins. In the present study, we explored the conditions under which glucose and ribose can glycate spectrin, both on the intact membrane and in solution and the functional consequences of spectrin glycation. While purified spectrin could be readily glycated, membrane-associated spectrin could be glycated only after ATP depletion and consequent translocation of phosphatidylserine (PS) from the inner to the outer lipid monolayer. Glycation of membrane-associated spectrin led to a marked decrease in membrane deformability. We further observed that only PS-binding spectrin repeats are glycated. We infer that the absence of glycation in situ is the consequence of the interaction of the target lysine and arginine residues with PS and thus being inaccessible for glycation. The reduced membrane deformability following glycation in the absence of ATP is likely the result of the inability of the glycated spectrin repeats to undergo the obligatory unfolding as a consequence of inter-helix crosslinks. We thus postulate that erythrocytes through the use of an ATP-driven phospholipids translocase have evolved a protective mechanism against spectrin glycation and thus maintain their optimal membrane function during their long circulatory life span.

人红细胞持续暴露于葡萄糖中，葡萄糖与血红蛋白链（Hb）的氨基末端发生反应，形成糖化血红蛋白（HbA1c），其水平随着循环细胞的年龄而增加。与血红蛋白糖化的广泛见解相反，对红细胞膜蛋白糖化知之甚少。在本研究中，我们探讨了葡萄糖和核糖在完整膜上和溶液中糖化spectrin的条件以及spectrin糖化的功能后果。纯化的谱蛋白可以很容易地被糖基化，而膜相关的谱蛋白只有在ATP耗尽和随后磷脂酰丝氨酸（PS）从内到外脂质单层易位后才能被糖基化。膜相关谱蛋白的糖基化导致膜可变形性显著降低。我们进一步观察到，只有结合ps的谱蛋白重复序列被糖基化。我们推断，原位糖基化的缺失是赖氨酸和精氨酸残基与PS相互作用的结果，因此无法进行糖基化。在没有ATP的情况下，糖基化后膜的可变形性降低，可能是由于糖基化的谱蛋白重复序列由于螺旋交联而无法进行必要的展开。因此，我们假设红细胞通过使用atp驱动的磷脂转位酶已经进化出一种保护机制来对抗谱蛋白糖化，从而在其漫长的循环寿命中保持其最佳的膜功能。