EFFECTS OF SULFATE-IONS ON ALZHEIMER-BETA/A4 PEPTIDE ASSEMBLIES - IMPLICATIONS FOR AMYLOID FIBRIL PROTEOGLYCAN INTERACTIONS
EFFECTS OF SULFATE-IONS ON ALZHEIMER-BETA/A4 PEPTIDE ASSEMBLIES - IMPLICATIONS FOR AMYLOID FIBRIL PROTEOGLYCAN INTERACTIONS
复制标题
DOI：
10.1111/j.1471-4159.1992.tb08470.x
复制
发表时间：
1992-10-01
影响因子：
4.7
通讯作者：
KIRSCHNER, DA
中科院分区：
文献类型：
--
作者：
FRASER, PE;NGUYEN, JT;KIRSCHNER, DA
为了模拟硫酸化蛋白聚糖在淀粉样蛋白生成中的可能参与，我们研究了硫酸根离子、乙酰肝素和刚果红对阿尔茨海默病β/A4淀粉样蛋白衍生肽的构象和形态的影响。肽包括β/A4的残基11-28、13-28、15-28和11-25。负染色电子显微镜显示了β（11-28）、β（13-28）和β（11-25）（但不是β（15-28））的预制肽纤维状组装体的硫酸盐特异性倾向，其经历广泛的侧向聚集和轴向生长成大约0.1-0.2 μ m宽、大约20-30 μ m长的“粗纤维”。在低硫酸盐浓度（例如，5-50 mM），并且在与Na 2 HPO 4、Na 2SeO 4或NaCl相当的条件下不能再现。在生理离子强度的NaCl，原纤维聚集，观察到只有在5-50 mM的硫酸根离子。硒离子，与硫酸根离子相比，只诱导轴向和没有实质性的横向聚集的原纤维。X射线衍射表明，原始的交叉β肽构象保持不变;然而，硫酸盐结合确实产生了对照肽未记录到的强烈的约65埃双折射。这种新的反射可能是由于电子致密的硫酸盐沿着纤维的（长）轴周期性沉积所致。硫酸盐结合可以提供用于产生所观察到的横向和轴向聚集的额外原纤维的结合的位点。乙酰肝素与β（11-28）的结合也产生了广泛的聚集，表明体内硫酸化化合物可以促进粗纤维。淀粉样蛋白特异性的磺化染料刚果红，即使在硫酸根离子的存在下，也产生有限的聚集并减少原纤维的轴向生长。因此，静电相互作用在外源性化合物与淀粉样纤维的结合中是重要的。我们的研究结果表明，某些分子的硫酸基团，如糖胺聚糖，可能会影响淀粉样纤维的聚集和沉积，观察到广泛的老年斑和脑血管淀粉样蛋白沉积。
To model the possible involvement of sulfated proteoglycans in amyloidogenesis, we examined the influence of sulfate ions, heparan, and Congo red on the conformation and morphology of peptides derived from the Alzheimer beta/A4 amyloid protein. The peptides included residues 11-28, 13-28, 15-28, and 11-25 of beta/A4. Negative-stain electron microscopy revealed a sulfate-specific tendency of the preformed peptide fibrillar assemblies of beta(11-28), beta(13-28), and beta(11-25), but not beta(15-28), to undergo extensive lateral aggregation and axial growth into "macrofibers" that were approximately 0.1-0.2-mu-m wide by approximately 20-30-mu-m long. Such effects were observed at low sulfate concentrations (e.g., 5-50 mM) and could not be reproduced under comparable conditions with Na2HPO4, Na2SeO4, or NaCl. Macrofibers in NaCl were only observed at 1,000 mM. At physiological ionic strength of NaCl, fibril aggregation was observed only with addition of sulfate ions at 5-50 mM. Selenate ions, by contrast with sulfate ions, induced only axial and not substantial lateral aggregation of fibrils. X-ray diffraction indicated that the original cross-beta peptide conformation remained unchanged; however, sulfate binding did produce an intense approximately 65 angstrom meridional reflection not recorded with control peptides. This new reflection probably arises from the periodic deposition of the electron-dense sulfate along the (long) axis of the fibril. The sulfate binding could provide sites for the binding of additional fibrils that generate the observed lateral and axial aggregation. The binding of heparan to beta(11-28) also produced extensive aggregation, suggesting that in vivo sulfated compounds can promote macrofibers. The amyloid-specific, sulfonated dye Congo red, even in the presence of sulfate ions, produced limited aggregation and reduced axial growth of the fibrils. Therefore, electrostatic interactions are important in the binding of exogenous compounds to amyloid fibrils. Our findings suggest that the sulfate moieties of certain molecules, such as glycosaminoglycans, may affect the aggregation and deposition of amyloid fibrils that are observed as extensive deposits in senile plaques and cerebrovascular amyloid.