Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity
Engineering metal ion coordination to regulate amyloid fibril assembly and toxicity
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DOI：
10.1073/pnas.0702669104
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发表时间：
2007-08-14
影响因子：
11.1
通讯作者：
Lynn, David G.
中科院分区：
文献类型：
--
作者：
Dong, Jijun;Canfield, Jeffrey M.;Lynn, David G.
蛋白质和肽组装成淀粉样蛋白涉及从有益的表观遗传控制到病理病因学的功能。然而，调控生物活性的组装体的确切结构仍然不清楚。我们以前曾使用锌离子来调节与阿尔茨海默病相关的淀粉样蛋白13肽（A β）同源物的组装动力学和形态学。我们现在揭示了A β-CU 2+协调，肽自组装和神经元活力之间的相关性。通过使用A β，HHQKLVFFA或A β（13-21）的中心片段，其中含有与A β-金属离子结合有关的残基H13和H14，我们表明CU 2+与A β 3（13-21）及其K16 A突变体形成复合物，并且该复合物不自组装成原纤维，具有与人朊病毒蛋白PrP相似的结构。N-末端乙酰化和H14 A取代，Ac-A beta（13-21）H14 A，改变金属配位，允许Cu 2+加速组装成神经毒性纤维。这些结果表明，A β的N-末端区域可以进入不同的金属离子配位环境，并且不同的络合物可以导致A β自组装动力学、形态和毒性的深刻变化。相关的金属离子配位可能是其他神经再生疾病的病因学的关键。
Protein and peptide assembly into amyloid has been implicated in functions that range from beneficial epigenetic controls to pathological etiologies. However, the exact structures of the assemblies that regulate biological activity remain poorly defined. We have previously used Zn2+ to modulate the assembly kinetics and morphology of congeners of the amyloid 13 peptide (A beta) associated with Alzheimer's disease. We now reveal a correlation among A beta-CU2+ coordination, peptide self-assembly, and neuronal viability. By using the central segment of A beta, HHQKLVFFA or A beta(13-21), which contains residues H13 and H14 implicated in A beta-metal ion binding, we show that CU2+ forms complexes with A)3(13-21) and its K16A mutant and that the complexes, which do not self-assemble into fibrils, have structures similar to those found for the human prion protein, PrP. N-terminal acetylation and H14A substitution, Ac-A beta(13-21)H14A, alters metal coordination, allowing Cu2+ to accelerate assembly into neurotoxic fibrils. These results establish that the N-terminal region of A beta can access different metal-ion-coordination environments and that different complexes can lead to profound changes in A beta self-assembly kinetics, morphology, and toxicity. Related metal-ion coordination may be critical to the etiology of other neuroclegenerative diseases.