Liquid Droplet Aging and Seeded Fibril Formation of the Cytotoxic Granule Associated RNA Binding Protein TIA1 Low Complexity Domain.
Liquid Droplet Aging and Seeded Fibril Formation of the Cytotoxic Granule Associated RNA Binding Protein TIA1 Low Complexity Domain.
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DOI：
10.1021/jacs.2c08596
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发表时间：
2023-01-25
影响因子：
15
通讯作者：
Murray, Dylan T.
中科院分区：
文献类型：
--
作者：
Wittmer, Yuuki;Jami, Khaled M.;Stowell, Rachelle K.;Le, Truc;Hung, Ivan;Murray, Dylan T.
偏向于少数氨基酸类型的蛋白质结构域对于活细胞中生物分子凝聚物的形成至关重要。这些无膜区室由表现出一系列分子运动和结构顺序的分子形成。错义突变增加了凝聚物的持久寿命或结构顺序，这些特性被认为是病理性蛋白质聚集的基础。在与神经退行性疾病相关的应激颗粒的背景下，该过程涉及将蛋白质液滴硬化成富含β链的蛋白质原纤维。在这里，我们描述了细胞毒性颗粒相关 RNA 结合蛋白 TIA1 (TIA1) 应激颗粒蛋白的低复杂性域液滴硬化的分子机制，以及与神经退行性疾病相关的疾病突变的影响。接种程序和固态核磁共振测量表明，低复杂性域收敛于由 21% 的序列组成的富含 β 链的原纤维构象。额外的固态核磁共振测量和差异光谱表明，野生型的老化液滴和脯氨酸-亮氨酸突变体低复杂性结构域由构象异质且结构不同于种子原纤维制剂的原纤维组装体组成。关于低复杂性领域，我们的数据支持功能模板驱动的构象均质结构的形成，将液滴刚性化为构象异质结构促进病理相互作用，并且疾病突变的影响比增加热力学稳定性或增加β链结构含量更加微妙。
Protein domains biased toward a few amino acid types are vital for the formation of biomolecular condensates in living cells. These membraneless compartments are formed by molecules exhibiting a range of molecular motions and structural order. Missense mutations increase condensate persistence lifetimes or structural order, properties that are thought to underlie pathological protein aggregation. In the context of stress granules associated with neurodegenerative diseases, this process involves the rigidification of protein liquid droplets into β-strand rich protein fibrils. Here, we characterize the molecular mechanism underlying the rigidification of liquid droplets for the low complexity domain of the Cytotoxic granule associated RNA binding protein TIA1 (TIA1) stress granule protein and the influence of a disease mutation linked to neurodegenerative diseases. A seeding procedure and solid state nuclear magnetic resonance measurements show that the low complexity domain converges on a β-strand rich fibril conformation composed of 21% of the sequence. Additional solid state nuclear magnetic resonance measurements and difference spectroscopy show that aged liquid droplets of wild type and a proline-to-leucine mutant low complexity domain are composed of fibril assemblies that are conformationally heterogeneous and structurally distinct from the seeded fibril preparation. Regarding low complexity domains, our data support the functional template-driven formation of conformationally homogeneous structures, that rigidification of liquid droplets into conformationally heterogenous structures promotes pathological interactions, and that the effect of disease mutations is more nuanced than increasing thermodynamic stability or increasing β-strand structure content.
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影响因子：
5.6
作者：
Fomicheva A;Ross ED
通讯作者：
Ross ED
低复杂性蛋白段的原子结构揭示了组装网络的扭结β薄片。
DOI：
10.1126/science.aan6398
发表时间：
2018-02-09
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hughes MP;Sawaya MR;Boyer DR;Goldschmidt L;Rodriguez JA;Cascio D;Chong L;Gonen T;Eisenberg DS
通讯作者：
Eisenberg DS
肌萎缩性侧索硬化和额颞痴呆的TIA1突变促进相位分离并改变应激颗粒动力学。
影响因子：
16.2
作者：
Mackenzie IR;Nicholson AM;Sarkar M;Messing J;Purice MD;Pottier C;Annu K;Baker M;Perkerson RB;Kurti A;Matchett BJ;Mittag T;Temirov J;Hsiung GR;Krieger C;Murray ME;Kato M;Fryer JD;Petrucelli L;Zinman L;Weintraub S;Mesulam M;Keith J;Zivkovic SA;Hirsch-Reinshagen V;Roos RP;Züchner S;Graff-Radford NR;Petersen RC;Caselli RJ;Wszolek ZK;Finger E;Lippa C;Lacomis D;Stewart H;Dickson DW;Kim HJ;Rogaeva E;Bigio E;Boylan KB;Taylor JP;Rademakers R
通讯作者：
Rademakers R
DOI：
10.1042/bcj20160499
发表时间：
2017-04-07
期刊：
The Biochemical journal
影响因子：
--
作者：
Harrison AF;Shorter J
通讯作者：
Shorter J
影响因子：
16.6
作者：
Li Q;Babinchak WM;Surewicz WK
通讯作者：
Surewicz WK