Functional amyloid formation within mammalian tissue.
Functional amyloid formation within mammalian tissue.
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DOI：
10.1371/journal.pbio.0040006
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发表时间：
2006-01
期刊：
影响因子：
9.8
通讯作者：
Kelly JW
中科院分区：
文献类型：
--
作者：
Fowler DM;Koulov AV;Alory-Jost C;Marks MS;Balch WE;Kelly JW
淀粉样蛋白通常是不溶性的纤维状交叉β折叠蛋白聚集体。淀粉样蛋白生成的过程与多种神经变性疾病相关，包括阿尔茨海默病、帕金森病和亨廷顿病。我们报告发现了一个前所未有的功能性哺乳动物淀粉样蛋白结构产生的蛋白Pmel 17。这一发现表明，淀粉样蛋白是一种基本的非病理性蛋白质折叠，被从细菌到人类的生物体所利用。我们已经发现，Pmel 17淀粉样蛋白模板，并加速共价聚合反应小分子成黑色素-一个至关重要的生物聚合物，防止广泛的细胞毒性损伤，包括紫外线和氧化损伤。Pmel 17淀粉样蛋白似乎还通过隔离和最小化高反应性毒性黑色素前体从黑素体中的扩散而在减轻与黑色素形成相关的毒性中起作用。细胞内Pmel 17淀粉样蛋白生成是通过分泌途径精心策划的，利用膜封存和蛋白水解步骤来保护细胞免受可能有毒的淀粉样蛋白和淀粉样蛋白生成中间体的影响。虽然功能性和病理性淀粉样蛋白具有相似的结构特征，但包装和组装动力学的关键差异使Pmel 17淀粉样蛋白能够用于正常功能。哺乳动物中天然Pmel 17淀粉样蛋白的发现为黑色素形成和淀粉样蛋白病理学的分子基础提供了关键的见解，并证明天然淀粉样蛋白（淀粉样蛋白）可能是一种古老的、进化上保守的蛋白质四级结构，支撑着促进正常细胞和组织生理学的多种途径。作者表明，在哺乳动物黑素体中发现的天然Pmel 17淀粉样蛋白加速黑素合成。
Amyloid is a generally insoluble, fibrous cross-β sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin—a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology. The authors show that native Pmel17 amyloid found in mammalian melanosomes accelerates melanin synthesis.
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DOI：
10.1034/j.1600-0749.13.s8.7.x
发表时间：
2000-01-01
期刊：
PIGMENT CELL RESEARCH
影响因子：
--
作者：
Hearing, VJ
通讯作者：
Hearing, VJ
影响因子：
11.4
作者：
Chen, CD;Huff, ME;Balch, WE
通讯作者：
Balch, WE
影响因子：
5.6
作者：
Lashuel, HA;Petre, BM;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
3.5
作者：
Linke, RP
通讯作者：
Linke, RP
影响因子：
64.8
作者：
Lashuel, HA;Hartley, D;Lansbury, PT
通讯作者：
Lansbury, PT