Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles.
Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles.
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DOI：
10.1073/pnas.2104148118
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发表时间：
2021-09-07
影响因子：
11.1
通讯作者：
Xue WF
中科院分区：
文献类型：
--
作者：
Koloteva-Levine N;Aubrey LD;Marchante R;Purton TJ;Hiscock JR;Tuite MF;Xue WF
与疾病相关的纤维状淀粉样结构的形成可以通过预先形成的淀粉样蛋白种子来加速。这种接种过程被认为仅通过淀粉样蛋白原纤维末端的伸长发生，导致种子中编码的蛋白质构象的模板化繁殖。我们证明，淀粉样蛋白播种并不总是通过模板化延伸进行，并表明淀粉样蛋白种子是纳米颗粒，可以加速新的异源淀粉样蛋白的形成，而不模板化种子中编码的蛋白质构象。我们提供了实验测试的标准，以区分播种通过模板化的延伸机制，从表面催化和目前的机械见解的淀粉样蛋白播种和交叉播种现象。这些发现对我们理解淀粉样蛋白交叉作用的分子基础具有广泛的意义。淀粉样蛋白种子是纳米大小的蛋白质颗粒，其加速淀粉样蛋白组装以及传播和传递与广泛的蛋白质错误折叠疾病相关的淀粉样蛋白构象。然而，种子淀粉样蛋白的生长，通过模板化的延伸在原纤维末端不能解释整个分子行为的过程中观察到的异源种子的淀粉样蛋白的交叉接种形成。在这里，我们证明了淀粉样蛋白种子可以通过表面催化机制加速淀粉样蛋白的形成，而不传播与种子相关的特定淀粉样蛋白构象。通过对涉及两种非同源和不相关蛋白质（人Aβ42肽和酵母朊病毒形成蛋白Sup35NM）的交叉接种组装反应进行定量表征，证明了这种接种机制。我们的研究结果表明，实验方法来区分播种的模板化延伸从nontemplated淀粉样蛋白播种和合理化的分子机制的交叉播种现象的表现异常的表面活性淀粉样蛋白种子作为纳米粒子。
The formation of disease-associated fibrillar amyloid structures can be accelerated by preformed amyloid seeds. This seeding process is thought to occur solely through elongation at amyloid fibril ends, resulting in the templated propagation of the protein conformation encoded in the seeds. We demonstrate that amyloid seeding does not always proceed through templated elongation and show that amyloid seeds are nanoparticles that can accelerate the formation of new heterologous amyloid without templating the protein conformation encoded in the seeds. We provide experimentally testable criteria to distinguish seeding through a templated elongation mechanism from surface catalysis and present mechanistic insights into the amyloid seeding and cross-seeding phenomenon. These findings have wide implications for our understanding of the molecular basis of amyloid cross-interactions. Amyloid seeds are nanometer-sized protein particles that accelerate amyloid assembly as well as propagate and transmit the amyloid protein conformation associated with a wide range of protein misfolding diseases. However, seeded amyloid growth through templated elongation at fibril ends cannot explain the full range of molecular behaviors observed during cross-seeded formation of amyloid by heterologous seeds. Here, we demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This type of seeding mechanism is demonstrated through quantitative characterization of the cross-seeded assembly reactions involving two nonhomologous and unrelated proteins: the human Aβ42 peptide and the yeast prion–forming protein Sup35NM. Our results demonstrate experimental approaches to differentiate seeding by templated elongation from nontemplated amyloid seeding and rationalize the molecular mechanism of the cross-seeding phenomenon as a manifestation of the aberrant surface activities presented by amyloid seeds as nanoparticles.
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影响因子：
9.8
作者：
Collins SR;Douglass A;Vale RD;Weissman JS
通讯作者：
Weissman JS
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：
4.8
作者：
Daniele S;Frosini D;Pietrobono D;Petrozzi L;Lo Gerfo A;Baldacci F;Fusi J;Giacomelli C;Siciliano G;Trincavelli ML;Franzoni F;Ceravolo R;Martini C;Bonuccelli U
通讯作者：
Bonuccelli U
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
--
作者：
Frederick, Kendra K.;Debelouchina, Galia T.;Lindquist, Susan
通讯作者：
Lindquist, Susan