Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers.
Mapping the sequence specificity of heterotypic amyloid interactions enables the identification of aggregation modifiers.
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DOI：
10.1038/s41467-022-28955-9
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发表时间：
2022-03-15
影响因子：
16.6
通讯作者：
Schymkowitz J
中科院分区：
文献类型：
--
作者：
Louros N;Ramakers M;Michiels E;Konstantoulea K;Morelli C;Garcia T;Moonen N;D'Haeyer S;Goossens V;Thal DR;Audenaert D;Rousseau F;Schymkowitz J
相关蛋白序列之间的异型淀粉样蛋白相互作用已在功能淀粉样蛋白和疾病淀粉样蛋白中观察到。虽然序列同源性似乎有利于异型淀粉样蛋白相互作用，但我们对决定这种相互作用的结构规则以及它们是否抑制或促进淀粉样蛋白组装没有系统的了解。利用基于结构的热力学计算和广泛的实验验证，我们对淀粉样蛋白相互作用中序列混杂的定义作用进行了全面的探索。利用tau作为模型系统，我们证明了与tau淀粉样蛋白成核区同源的局部序列蛋白可以改变培养细胞中原纤维的成核、形态、聚集体的组装和扩散。根据突变的类型，这种相互作用以一种可以从结构中预测的方式抑制或促进聚集。我们发现这些异型淀粉样蛋白相互作用可导致这些蛋白质的亚细胞错定位。此外，平衡研究表明，聚集的临界浓度会因异型相互作用而改变。我们的研究结果表明，蛋白质组学背景可以调节淀粉样蛋白聚集倾向的结构机制，我们讨论了这种序列特异性的蛋白质静态扰动如何有助于淀粉样蛋白疾病进展的选择性细胞易感性。在这项工作中，Louros等人发现了淀粉样蛋白与其他蛋白质相互作用的规则手册。该语法被证明可以促进细胞中tau聚集体的细胞扩散，但也可以用于开发基于结构的聚集体阻滞剂。
Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic amyloid interactions, we have no systematic understanding of the structural rules determining such interactions nor whether they inhibit or facilitate amyloid assembly. Using structure-based thermodynamic calculations and extensive experimental validation, we performed a comprehensive exploration of the defining role of sequence promiscuity in amyloid interactions. Using tau as a model system we demonstrate that proteins with local sequence homology to tau amyloid nucleating regions can modify fibril nucleation, morphology, assembly and spreading of aggregates in cultured cells. Depending on the type of mutation such interactions inhibit or promote aggregation in a manner that can be predicted from structure. We find that these heterotypic amyloid interactions can result in the subcellular mis-localisation of these proteins. Moreover, equilibrium studies indicate that the critical concentration of aggregation is altered by heterotypic interactions. Our findings suggest a structural mechanism by which the proteomic background can modulate the aggregation propensity of amyloidogenic proteins and we discuss how such sequence-specific proteostatic perturbations could contribute to the selective cellular susceptibility of amyloid disease progression. In this work, Louros et al. uncover a rule book for interactions of amyloids with other proteins. This grammar was shown to promote cellular spreading of tau aggregates in cells, but can also be harvested to develop structure-based aggregation blockers.
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影响因子：
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作者：
Collinson, SK;Parker, JMR;Kay, WW
通讯作者：
Kay, WW
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作者：
Benkemoun, Laura;Ness, Frederique;Saupe, Sven J.
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Saupe, Sven J.
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Masliah, E