Molecular structure and interactions within amyloid-like fibrils formed by a low-complexity protein sequence from FUS.
Molecular structure and interactions within amyloid-like fibrils formed by a low-complexity protein sequence from FUS.
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DOI：
10.1038/s41467-020-19512-3
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发表时间：
2020-11-12
影响因子：
16.6
通讯作者：
Tycko R
中科院分区：
文献类型：
--
作者：
Lee M;Ghosh U;Thurber KR;Kato M;Tycko R
没有通常的氨基酸分布的蛋白质结构域，称为低复杂性（LC）结构域，可以倾向于自组装成淀粉样原纤维。几乎没有疏水残基的LC结构域的自组装，例如RNA结合蛋白FUS的214-残基LC结构域，从生物物理学的角度来看是特别有趣的，并且由于其在肌萎缩侧索硬化症、额颞叶痴呆和其他神经退行性疾病中的神经元内的发生而具有生物医学相关性。我们基于冷冻电子显微镜（cryo-EM）获得的分辨率为2.62 Å的密度图，报告了由FUS LC结构域C末端一半（FUS-LC-C，残基111-214）形成的原纤维的高分辨率分子结构模型。在FUS-LC-C原纤维核心中，残基112-150采用U形构象并形成具有准21对称性排列的对齐的平行交叉β结构的两个亚基。全原子分子动力学模拟表明，FUS-LC-C原纤维核心是由大量的氢键稳定的，这些氢键涉及Gln、Asn、Ser和Tyr残基的侧链，沿着和横向于原纤维生长方向，包括不同的侧链-主链、侧链-侧链和侧链-水相互作用。核磁共振测量另外显示，无序残基151-214的部分在FUS-LC-C原纤维中保持高度动态，并且由FUS LC结构域的N-末端一半（FUS-LC-N，残基2-108）形成的原纤维具有与由全长LC结构域形成的原纤维相同的核心结构。这些结果有助于我们理解淀粉样蛋白形成的分子结构基础FUS和LC域一般。低复杂性（LC）结构域介导RNA结合蛋白FUS（FUsed in Sarcoma）的液-液相分离和原纤维形成。在这里，作者结合联合收割机cryo-EM，固态NMR测量和MD模拟，在结构上形成的FUS LC域的C-末端的一半，并讨论稳定的原纤维核心内的相互作用。
Protein domains without the usual distribution of amino acids, called low complexity (LC) domains, can be prone to self-assembly into amyloid-like fibrils. Self-assembly of LC domains that are nearly devoid of hydrophobic residues, such as the 214-residue LC domain of the RNA-binding protein FUS, is particularly intriguing from the biophysical perspective and is biomedically relevant due to its occurrence within neurons in amyotrophic lateral sclerosis, frontotemporal dementia, and other neurodegenerative diseases. We report a high-resolution molecular structural model for fibrils formed by the C-terminal half of the FUS LC domain (FUS-LC-C, residues 111-214), based on a density map with 2.62 Å resolution from cryo-electron microscopy (cryo-EM). In the FUS-LC-C fibril core, residues 112-150 adopt U-shaped conformations and form two subunits with in-register, parallel cross-β structures, arranged with quasi-21 symmetry. All-atom molecular dynamics simulations indicate that the FUS-LC-C fibril core is stabilized by a plethora of hydrogen bonds involving sidechains of Gln, Asn, Ser, and Tyr residues, both along and transverse to the fibril growth direction, including diverse sidechain-to-backbone, sidechain-to-sidechain, and sidechain-to-water interactions. Nuclear magnetic resonance measurements additionally show that portions of disordered residues 151-214 remain highly dynamic in FUS-LC-C fibrils and that fibrils formed by the N-terminal half of the FUS LC domain (FUS-LC-N, residues 2-108) have the same core structure as fibrils formed by the full-length LC domain. These results contribute to our understanding of the molecular structural basis for amyloid formation by FUS and by LC domains in general. The low-complexity (LC) domain mediates liquid-liquid phase separation and fibril formation of the RNA-binding protein FUS (FUsed in Sarcoma). Here, the authors combine cryo-EM, solid-state NMR measurements and MD simulations to structurally characterise the fibrils formed by the C-terminal half of the FUS LC domain and discuss stabilizing interactions within the fibril core.
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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
DOI：
10.1126/science.aao2825
发表时间：
2017-10-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gremer L;Schölzel D;Schenk C;Reinartz E;Labahn J;Ravelli RBG;Tusche M;Lopez-Iglesias C;Hoyer W;Heise H;Willbold D;Schröder GF
通讯作者：
Schröder GF
影响因子：
4.4
作者：
BENNETT, AE;RIENSTRA, CM;GRIFFIN, RG
通讯作者：
GRIFFIN, RG
影响因子：
16.8
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
通讯作者：
Eisenberg, David S.
DOI：
10.1073/pnas.96.7.3590
发表时间：
1999-03-30
影响因子：
11.1
作者：
Chiti, F;Webster, P;Dobson, CM
通讯作者：
Dobson, CM