CLAC binds to amyloid β peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils
CLAC binds to amyloid β peptides through the positively charged amino acid cluster within the collagenous domain 1 and inhibits formation of amyloid fibrils
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DOI：
10.1074/jbc.m413340200
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发表时间：
2005-03-04
影响因子：
4.8
通讯作者：
Iwatsubo, T
中科院分区：
文献类型：
--
作者：
Osada, Y;Hashimoto, T;Iwatsubo, T
CLAC(胶原性阿尔茨海默病淀粉样斑块成分)是一种新的膜结合胶原CLAC-P/胶原XXV型蛋白水解物，它沉积在阿尔茨海默病患者大脑中与淀粉样β多肽(Abeta)相关的老年斑中。我们之前的研究表明，CLAC在体外可以与纤化形式的Abeta结合，但介导CLAC与Abeta相互作用的机制和亚域以及CLAC结合对淀粉样原纤维形成的影响尚不清楚。在这里，我们证明了CLAC的胶原区1富含正电荷的氨基酸残基，介导了它与Abeta的相互作用，这种结合是由静电相互作用介导的，需要形成CLAC的三螺旋结构。从转染CLAC-P的细胞培养上清液中提纯的可溶性CLAC在体外可抑制Abeta的纤化，尤其是在其延伸期。这些结果表明，CLAC在阿尔茨海默病的病理生理学中具有抗淀粉样变性作用。
CLAC ( collagenous Alzheimer amyloid plaque component) is a proteolytic fragment derived from a novel membrane-bound collagen, CLAC-P/collagen type XXV, that deposits in senile plaques associated with amyloid beta peptides (Abeta) in the brains of patients with Alzheimer's disease. We previously showed that CLAC binds to the fibrillized form of Abeta in vitro, although the mechanism and the subdomains that mediate interaction of CLAC with Abeta as well as the effect of binding of CLAC on amyloid fibril formation remain unknown. Here we show that the collagenous domain 1 of CLAC, which is rich in positively charged amino acid residues, mediates its interaction with Abeta and that this binding is mediated by an electrostatic interaction and requires formation of the triple helix structure of CLAC. The soluble form of CLAC purified from the media of cells transfected with CLAC-P inhibited fibrillization of Abeta in vitro, especially in its elongation phase. These results suggest the anti-amyloidogenic roles of CLAC in the pathophysiology of Alzheimer's disease.