Ezzat Kariem, Sturchio Andrea, Espay Alberto J
Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, 141 57 Stockholm, Sweden.
Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institutet, 171 76 Stockholm, Sweden.
Biology (Basel). 2022 Mar 30;11(4):535. doi: 10.3390/biology11040535.
Protein aggregation into amyloid fibrils affects many proteins in a variety of diseases, including neurodegenerative disorders, diabetes, and cancer. Physicochemically, amyloid formation is a phase transition process, where soluble proteins are transformed into solid fibrils with the characteristic cross-β conformation responsible for their fibrillar morphology. This phase transition proceeds via an initial, rate-limiting nucleation step followed by rapid growth. Several well-defined nucleation pathways exist, including homogenous nucleation (HON), which proceeds spontaneously; heterogeneous nucleation (HEN), which is catalyzed by surfaces; and seeding via preformed nuclei. It has been hypothesized that amyloid aggregation represents a protein-only (nucleic-acid free) replication mechanism that involves transmission of structural information via conformational templating (the prion hypothesis). While the prion hypothesis still lacks mechanistic support, it is also incompatible with the fact that proteins can be induced to form amyloids in the absence of a proteinaceous species acting as a conformational template as in the case of HEN, which can be induced by lipid membranes (including viral envelopes) or polysaccharides. Additionally, while amyloids can be formed from any protein sequence and via different nucleation pathways, they invariably adopt the universal cross-β conformation; suggesting that such conformational change is a spontaneous folding event that is thermodynamically favorable under the conditions of supersaturation and phase transition and not a templated replication process. Finally, as the high stability of amyloids renders them relatively inert, toxicity in some amyloid pathologies might be more dependent on the loss of function from protein sequestration in the amyloid state rather than direct toxicity from the amyloid plaques themselves.
蛋白质聚集成淀粉样纤维在多种疾病中影响许多蛋白质，包括神经退行性疾病、糖尿病和癌症。从物理化学角度来看，淀粉样蛋白形成是一个相变过程，其中可溶性蛋白质转变为具有特征性交叉β构象的固体纤维，这种构象决定了它们的纤维形态。这个相变过程通过一个初始的、限速的成核步骤，随后是快速生长。存在几种明确的成核途径，包括自发进行的均相成核（HON）；由表面催化的异相成核（HEN）；以及通过预先形成的核进行的种子接种。据推测，淀粉样蛋白聚集代表一种仅涉及蛋白质（无核酸）的复制机制，该机制通过构象模板传递结构信息（朊病毒假说）。虽然朊病毒假说仍然缺乏机制支持，但它也与以下事实不相符：在没有作为构象模板的蛋白质物种的情况下，蛋白质也能被诱导形成淀粉样蛋白，例如在脂质膜（包括病毒包膜）或多糖诱导的异相成核情况下。此外，虽然淀粉样蛋白可以由任何蛋白质序列通过不同的成核途径形成，但它们总是采用通用的交叉β构象；这表明这种构象变化是一种自发折叠事件，在过饱和和相变条件下在热力学上是有利的，而不是一个模板复制过程。最后，由于淀粉样蛋白的高稳定性使其相对惰性，某些淀粉样蛋白病变中的毒性可能更多地取决于淀粉样状态下蛋白质隔离导致的功能丧失，而不是淀粉样斑块本身的直接毒性。
