Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
Cellular Neuroscience, Neurodegeneration and Repair Program, Departments of Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Department of Chemistry, Yale University School of Medicine, New Haven, CT, USA.
Mol Cell. 2018 Nov 1;72(3):426-443.e12. doi: 10.1016/j.molcel.2018.10.009. Epub 2018 Oct 25.
Protein phase separation by low-complexity, intrinsically disordered domains generates membraneless organelles and links to neurodegeneration. Cellular prion protein (PrP) contains such domains, causes spongiform degeneration, and is a receptor for Alzheimer's amyloid-β oligomers (Aβo). Here, we show that PrP separates as a liquid phase, in which α-helical Thr become unfolded. At the cell surface, PrP Lys residues interact with Aβo to create a hydrogel containing immobile Aβo and relatively mobile PrP. The Aβo/PrP hydrogel has a well-defined stoichiometry and dissociates with excess Aβo. NMR studies of hydrogel PrP reveal a distinct α-helical conformation for natively unfolded amino-terminal Gly and Ala residues. Aβo/PrP hydrogel traps signal-transducing mGluR5 on the plasma membrane. Recombinant PrP extracts endogenous Aβo from human Alzheimer's soluble brain lysates into hydrogel, and a PrP antagonist releases Aβo from endogenous brain hydrogel. Thus, coupled phase and conformational transitions of PrP are driven by Aβ species from Alzheimer's disease.
低复杂度、固有无序域的蛋白质相分离产生无膜细胞器，并与神经退行性疾病有关。细胞朊病毒蛋白 (PrP) 含有此类结构域，可引起海绵状变性，是阿尔茨海默病淀粉样β寡聚体 (Aβo) 的受体。在这里，我们表明 PrP 作为液相分离，其中α-螺旋 Thr 展开。在细胞表面，PrP Lys 残基与 Aβo 相互作用形成含有固定 Aβo 和相对移动 PrP 的水凝胶。Aβo/PrP 水凝胶具有明确的化学计量比，并与过量的 Aβo 解离。水凝胶 PrP 的 NMR 研究揭示了天然无规卷曲氨基末端 Gly 和 Ala 残基的独特α-螺旋构象。Aβo/PrP 水凝胶会捕获质膜上的信号转导 mGluR5。重组 PrP 将人阿尔茨海默病可溶性脑组织裂解物中的内源性 Aβo 提取到水凝胶中，而 PrP 拮抗剂可将内源性脑水凝胶中的 Aβo 释放出来。因此，阿尔茨海默病 Aβ 物质驱动了 PrP 的偶联相和构象转变。
