PH-DEPENDENT BINDING OF SYNTHETIC BETA-AMYLOID PEPTIDES TO GLYCOSAMINOGLYCANS
PH-DEPENDENT BINDING OF SYNTHETIC BETA-AMYLOID PEPTIDES TO GLYCOSAMINOGLYCANS
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DOI：
10.1111/j.1471-4159.1993.tb07453.x
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发表时间：
1993-12-01
影响因子：
4.7
通讯作者：
FREDERICKSON, RCA
中科院分区：
文献类型：
--
作者：
BRUNDEN, KR;RICHTERCOOK, NJ;FREDERICKSON, RCA
阿尔茨海默病大脑的大脑皮质和海马内发现的老年斑含有β-淀粉样肽（Abeta）原纤维，这些原纤维与多种大分子物质相关，包括硫酸皮肤素蛋白聚糖和硫酸乙酰肝素蛋白聚糖。后者最近已被证明与淀粉样前体蛋白和Abeta紧密结合，这种结合主要归因于硫酸乙酰肝素蛋白聚糖的核心蛋白与Abeta及其前体的相互作用。在这里，我们已经检查了合成的Abetas与蛋白聚糖的糖胺聚糖部分结合并相互作用的能力。Abeta（1-28）与肝素、硫酸乙酰肝素、硫酸皮肤素和硫酸软骨素缔合。这些硫酸化多糖与淀粉样肽的相互作用导致形成大的聚集体，其易于通过离心沉淀。Abeta（1-28）和Abeta（1-40）结合糖胺聚糖的能力都是pH依赖性的，当pH值低于中性时相互作用增加，而在pH 8.0时几乎没有结合。肝素诱导的Abeta（1-28）聚集的pH曲线的中点pH约为6.5，表明一个或多个组氨酸残基必须质子化才能结合。对Abeta序列的分析揭示了在残基12-17处的共有肝素结合结构域，并且该基序在位置13和14处含有组氨酸，其可能参与与糖胺聚糖的相互作用。该假设得到以下观察结果的支持：（a）Abeta（13-17）在pH 4.0时与肝素亲和柱紧密结合，但在pH 8.0时不结合;（B）组氨酸残基13和14被丝氨酸取代的Abeta（13-17）在pH 8.0或4.0时均不与肝素柱结合。总之，这些数据表明，Abeta能够结合蛋白聚糖的糖胺聚糖链，这种相互作用可能与阿尔茨海默病的病因学和病理学有关。
The senile plaques found within the cerebral cortex and hippocampus of the Alzheimer disease brain contain beta-amyloid peptide (Abeta) fibrils that are associated with a variety of macromolecular species, including dermatan sulfate proteoglycan and heparan sulfate proteoglycan. The latter has been shown recently to bind tightly to both amyloid precursor protein and Abeta, and this binding has been attributed largely to the interaction of the core protein of heparan sulfate proteoglycan with Abeta and its precursor. Here we have examined the ability of synthetic Abetas to bind to and interact with the glycosaminoglycan moieties of proteoglycans. Abeta(1-28) associates with heparin, heparan sulfate, dermatan sulfate, and chondroitin sulfate. The interaction of these sulfated polysaccharides with the amyloid peptide results in the formation of large aggregates that are readily sedimented by centrifugation. The ability of both Abeta(1-28) and Abeta(1-40) to bind glycosaminoglycans is pH-dependent, with increasing interaction as the pH values fall below neutrality and very little binding at pH 8.0. The pH profile of heparin-induced aggregation of Abeta(1-28) has a midpoint pH of approximately 6.5, suggesting that one or more histidine residues must be protonated for binding to occur. Analysis of the Abeta sequence reveals a consensus heparin-binding domain at residues 12-17, and this motif contains histidines at positions 13 and 14 that may be involved in the interaction with glycosaminoglycans. This hypothesis is supported by the following observations: (a) Abeta(13-17) binds tightly to a heparin affinity column at pH 4.0, but not at pH 8.0; and (b) an Abeta(13-17) in which histidine residues 13 and 14 have been replaced with serines does not bind to a heparin column at either pH 8.0 or 4.0. Together, the data indicate that Abeta is capable of binding to the glycosaminoglycan chains of proteoglycans, and such an interaction may be relevant to the etiology and pathology of Alzheimer's disease.