Molecular structures of amyloid and prion fibrils: consensus versus controversy.
Molecular structures of amyloid and prion fibrils: consensus versus controversy.
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DOI：
10.1021/ar300282r
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发表时间：
2013-07-16
影响因子：
18.3
通讯作者：
Wickner, Reed B.
中科院分区：
文献类型：
--
作者：
Tycko, Robert;Wickner, Reed B.
许多肽和蛋白质自组装成淀粉样蛋白原纤维，包括与人类淀粉样蛋白疾病相关的多肽、哺乳动物和真菌朊病毒蛋白以及被认为具有生物学功能性淀粉样蛋白状态的蛋白质。正确理解多肽形成淀粉样蛋白原纤维的共同倾向取决于这些原纤维的分子结构的阐明，淀粉样蛋白抑制剂和成像剂的合理设计也是如此。15年前，淀粉样蛋白原纤维的结构还很神秘，但现在已经有了大量可靠的结构信息，固态核磁共振（NMR）测量也做出了重要贡献。本文回顾了我们实验室的结果，并讨论了几个结构性问题，一直是争议的来源。在许多情况下，淀粉样蛋白原纤维的分子结构并不是由其氨基酸序列唯一决定的。自传播的分子水平的多态性使结构测定问题复杂化，并且可能导致来自不同实验室的结果之间的明显不一致，而实际上不同实验室只是在研究不同的多晶型物。对于与阿尔茨海默病相关的40-残基β-淀粉样蛋白（Aβ1-40）原纤维，我们已经从固态NMR和电子显微镜数据中为两种多晶型物开发了详细的结构模型，我们发现它们具有相似的肽构象，相同的平行β-折叠组织，但不同的整体对称性。其他多晶型物也已通过固态NMR部分表征，并且似乎具有相似的结构。相比之下，使用显著不同的原纤维生长条件的低温电子显微镜研究已经鉴定出似乎（在低分辨率下）与通过固态NMR检查的那些不同的结构。通过固态NMR和电子顺磁共振（EPR），在β-淀粉样蛋白原纤维中发现的对齐平行β-折叠组织也已在许多其他原纤维形成系统中发现，并且可归因于通过类似氨基酸之间的分子间相互作用（包括疏水相互作用和极性拉链）稳定淀粉样蛋白结构。令人惊讶的是，在由Aβ1-40的D23 N突变体形成的某些原纤维中，已经通过固态NMR鉴定和表征了反平行β折叠，Aβ1-40的D23 N突变体与早发性家族性神经变性疾病相关。反平行D23 N-A β1-40原纤维在转化为平行结构方面是亚稳态的，因此代表淀粉样蛋白原纤维形成过程中的非途径中间体。最近通过其他方法获得了在其他淀粉样蛋白形成中间体中存在反平行β折叠的证据。作为简单的平行和反平行β折叠结构的替代，β螺旋结构模型已经被提出用于各种原纤维，特别是由哺乳动物和真菌朊病毒蛋白形成的那些。固态NMR和EPR数据表明，体外重组PrP形成的原纤维具有对齐的平行β-折叠结构，但感染性PrP聚集体的结构尚未明确。真菌HET-s朊病毒蛋白已通过固态NMR显示具有β-螺旋结构，但通过固态NMR研究的所有酵母朊病毒（即，Sup 35 p、Ure 2 p和Rnq 1 p）具有对齐的平行β-折叠结构，其中原纤维核心由其富含Gln和Asn的N-末端片段形成。
Many peptides and proteins self-assemble into amyloid fibrils, including polypeptides that are associated with human amyloid diseases, mammalian and fungal prion proteins, and proteins that are believed to have biologically functional amyloid states. Proper understanding of the common propensity for polypeptides to form amyloid fibrils depends on elucidation of the molecular structures of these fibrils, as does rational design of amyloid inhibitors and imaging agents. Whereas amyloid fibril structures were largely mysterious 15 years ago, a considerable body of reliable structural information now exists, with important contributions from solid state nuclear magnetic resonance (NMR) measurements. This article reviews results from our laboratories and discusses several structural issues that have been sources of controversy. In many cases, the molecular structures of amyloid fibrils are not determined uniquely by their amino acid sequences. Self-propagating, molecular-level polymorphism complicates the structure determination problem and can lead to apparent disagreements between results from different laboratories, when in fact different laboratories are simply studying different polymorphs. For 40-residue β-amyloid (Aβ1–40) fibrils associated with Alzheimer’s disease, we have developed detailed structural models from solid state NMR and electron microscopy data for two polymorphs, which we found to have similar peptide conformations, identical in-register parallel β-sheet organizations, but different overall symmetry. Other polymorphs have also been partially characterized by solid state NMR, and appear to have similar structures. In contrast, cryo-electron microscopy studies that use significantly different fibril growth conditions have identified structures that appear (at low resolution) to be different from those examined by solid state NMR. The in-register parallel β-sheet organization found in β-amyloid fibrils has also been found in many other fibril-forming systems by solid state NMR and electron paramagnetic resonance (EPR), and is attributable to stabilization of amyloid structures by intermolecular interactions among like amino acids, including hydrophobic interactions and polar zippers. Surprisingly, antiparallel β-sheets have been identified and characterized by solid state NMR in certain fibrils formed by the D23N mutant of Aβ1–40, which is associated with early-onset, familial neurodegenerative disease. Antiparallel D23N-Aβ1–40 fibrils are metastable with respect to conversion to parallel structures, and therefore represent an off-pathway intermediate in the amyloid fibril formation process. Evidence for antiparallel β-sheets in other amyloid-formation intermediates has been obtained recently by other methods. As an alternative to simple parallel and antiparallel β-sheet structures, β-helical structural models have been proposed for various fibrils, especially those formed by mammalian and fungal prion proteins. Solid state NMR and EPR data show that fibrils formed in vitro by recombinant PrP have in-register parallel β-sheet structures, but the structure of infectious PrP aggregates is not yet known definitively. The fungal HET-s prion protein has been shown by solid state NMR to have a β-helical structure, but all yeast prions studied by solid state NMR (i.e., Sup35p, Ure2p, and Rnq1p) have in-register parallel β-sheet structures, with the fibril core being formed by their Gln- and Asn-rich N-terminal segments.
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影响因子：
2.9
作者：
Baxa, Ulrich;Wickner, Reed B.;Tycko, Robert
通讯作者：
Tycko, Robert
DOI：
10.1073/pnas.0706522104
发表时间：
2007-11-27
影响因子：
11.1
作者：
Cobb, Nathan J.;Soennichsen, Frank D.;Surewicz, Witold K.
通讯作者：
Surewicz, Witold K.
影响因子：
2.9
作者：
Luca, Sorin;Yau, Wai-Ming;Tycko, Robert
通讯作者：
Tycko, Robert
DOI：
10.1073/pnas.95.23.13407
发表时间：
1998-11-10
影响因子：
11.1
作者：
Benzinger, TLS;Gregory, DM;Meredith, SC
通讯作者：
Meredith, SC
影响因子：
4.8
作者：
Bedrood, Sahar;Li, Yiyu;Langen, Ralf
通讯作者：
Langen, Ralf