Alzheimer's disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits
Alzheimer's disease amyloid-β binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits
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DOI：
10.1074/jbc.m100175200
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发表时间：
2001-06-08
影响因子：
4.8
通讯作者：
Barnham, KJ
中科院分区：
文献类型：
--
作者：
Curtain, CC;Ali, F;Barnham, KJ
淀粉样β肽（A β）是细胞外斑块和血管周围淀粉样沉积物的主要成分，是阿尔茨海默病的特征性神经病理学病变。Gu（2+）和Zn 2+结合A β，诱导聚集并产生活性氧。这些反应可能在疾病状态中起有害作用，因为高浓度的铁、铜和锌已位于患病大脑的淀粉样蛋白中。在这里，我们表明，在水溶液和脂质环境中，金属离子与A β的配位是相同的，His（6），His（13）和His（14）都参与其中。在Cu 2 +/肽摩尔比>0.3时，A β以高度合作的方式与第二个Cu 2+原子配位。如果组氨酸残基甲基化，则这种效应被消除。N-ε 2，表明存在桥连组氨酸残基，如在超氧化物歧化酶的活性位点中发现的。在带负电荷的脂质环境中向A β中添加Cu 2+或Zn 2+引起从β-折叠到α-螺旋的构象变化，伴随着肽寡聚化和膜穿透，这些结果表明，金属结合到A β产生了一个变构有序的膜穿透低聚物连接的超氧化物歧化酶样桥接组氨酸残基。
Amyloid beta peptide (A beta) is the major constituent of extracellular plaques and perivascular amyloid deposits, the pathognomonic neuropathological lesions of Alzheimer's disease. Gu(2+) and Zn2+ bind A beta, inducing aggregation and giving rise to reactive oxygen species. These reactions may play a deleterious role in the disease state, because high concentrations of iron, copper, and zinc have been located in amyloid in diseased brains. Here we show that coordination of metal ions to A beta is the same in both aqueous solution and lipid environments, with His(6), His(13), and His(14) all involved. At Cu2+/peptide molar ratios >0.3, A beta coordinated a second Cu2+ atom in a highly cooperative manner. This effect was abolished if the histidine residues were methylated at. N-epsilon2, indicating the presence of bridging histidine residues, as found in the active site of superoxide dismutase, Addition of Cu2+ Or Zn2+ to A beta in a negatively charged lipid environment caused a conformational change from beta -sheet to alpha -helix, accompanied by peptide oligomerization and membrane penetration, These results suggest that metal binding to A beta generated an allosterically ordered membrane-penetrating oligomer linked by superoxide dismutase-like bridging histidine residues.