Tubulin-binding region alters tau-lipid interactions and changes toxicity of tau fibrils formed in the presence of phosphatidylserine lipids.

IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Protein Science Pub Date : 2024-07-01 DOI:10.1002/pro.5078
Abid Ali, Aidan P Holman, Axell Rodriguez, Mikhail Matveyenka, Dmitry Kurouski
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Abstract

Alzheimer's disease is the fastest-growing neurodegenerative disease that affects over six million Americans. The abnormal aggregation of amyloid β peptide and Tau protein is the expected molecular cause of the loss of neurons in brains of AD patients. A growing body of evidence indicates that lipids can alter the aggregation rate of amyloid β peptide and modify the toxicity of amyloid β aggregates. However, the role of lipids in Tau aggregation remains unclear. In this study, we utilized a set of biophysical methods to determine the extent to which phospatidylserine (PS) altered the aggregation properties of Tau isoforms with one (1N4R) and two (2N4R) N terminal inserts that enhance the binding of Tau to tubulin. We found that the length and saturation of fatty acids (FAs) in PS altered the aggregation rate of 2N4R isoform, while no changes in the aggregation rate of 1N4R were observed. These results indicate that N terminal inserts play an important role in protein-lipid interactions. We also found that PS could change the toxicity of 1N4R and 2N4R Tau fibrils, as well as alter molecular mechanisms by which these aggregates exert cytotoxicity to neurons. Finally, we found that although Tau fibrils formed in the presence and absence of PS endocytosed by cells, only fibril species that were formed in the presence of PS exert strong impairment of the cell mitochondria.

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微管蛋白结合区改变了 tau 与脂质的相互作用,并改变了在磷脂酰丝氨酸脂质存在下形成的 tau 纤维的毒性。
阿尔茨海默病是发展最快的神经退行性疾病,影响着六百多万美国人。淀粉样β肽和Tau蛋白的异常聚集是导致阿尔茨海默病患者大脑神经元丧失的预期分子原因。越来越多的证据表明,脂质可以改变淀粉样β肽的聚集率,并改变淀粉样β聚集体的毒性。然而,脂质在Tau聚集中的作用仍不清楚。在这项研究中,我们利用一套生物物理方法来确定磷脂酰丝氨酸(PS)在多大程度上改变了具有一个(1N4R)和两个(2N4R)N末端插入物的Tau异构体的聚集特性,这些插入物增强了Tau与小管蛋白的结合。我们发现 PS 中脂肪酸(FA)的长度和饱和度会改变 2N4R 异构体的聚集率,而 1N4R 的聚集率没有变化。这些结果表明,N 端插入物在蛋白质与脂质的相互作用中发挥着重要作用。我们还发现 PS 可以改变 1N4R 和 2N4R Tau 纤维的毒性,并改变这些聚集体对神经元产生细胞毒性的分子机制。最后,我们发现,虽然细胞在有 PS 和无 PS 的情况下都能内吞形成 Tau 纤维,但只有在有 PS 的情况下形成的纤维种类才会对细胞线粒体造成强烈损害。
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来源期刊
Protein Science
Protein Science 生物-生化与分子生物学
CiteScore
12.40
自引率
1.20%
发文量
246
审稿时长
1 months
期刊介绍: Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).
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