神经性病原体对认知的影响:通过计算方法研究分子模仿。

IF 3.6 4区 医学 Q3 CELL BIOLOGY Cellular and Molecular Neurobiology Pub Date : 2024-10-29 DOI:10.1007/s10571-024-01509-x
Pascal Büttiker, Amira Boukherissa, Simon Weissenberger, Radek Ptacek, Martin Anders, Jiri Raboch, George B Stefano
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引用次数: 0

摘要

神经性病原体,尤其是疱疹病毒,与严重的神经精神影响有关。作为一个群体,这些病原体可以利用分子模拟机制来操纵宿主的中枢神经系统,使其对宿主有利。在这里,我们提出了一种系统的计算方法,最终可用于揭示尚未通过实验解决的蛋白质-蛋白质相互作用和分子模拟过程。为此,我们通过复制一组已有的实验结果来验证这种方法,这些实验结果记录了人类巨细胞病毒编码的 UL144 糖蛋白与人类肿瘤坏死因子受体超家族成员 14 (TNFRSF14) 在结构和功能上的相似性。我们首先使用基本局部比对搜索工具(BLASTx)对智人蛋白质数据库进行了彻底的探索,以确定与 UL144 有序列同源性的蛋白质。随后,我们使用 AlphaFold2 预测了 UL144 和 TNFRSF14 的独立三维结构。随后,我们利用距离矩阵比对和 Foldseek 进行了全面的结构比较。最后,我们使用 AlphaFold-multimer 和 PPIscreenML 阐明了潜在的蛋白质复合物,并确认了 UL144 和 TNFRSF14 的预测结合活性。然后,我们利用硅学方法复制了实验结果,发现 TNFRSF14 同时与 B 淋巴细胞和 T 淋巴细胞衰减因子(BTLA)和糖蛋白结构域结合,而 UL144 仅与 BTLA 结合。这一计算框架有望确定病原体编码蛋白与其宿主对应蛋白之间的结构相似性和相互作用。这些信息将为了解病毒感染对神经精神影响的认知机制提供宝贵的见解。
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Cognitive Impact of Neurotropic Pathogens: Investigating Molecular Mimicry through Computational Methods.

Neurotropic pathogens, notably, herpesviruses, have been associated with significant neuropsychiatric effects. As a group, these pathogens can exploit molecular mimicry mechanisms to manipulate the host central nervous system to their advantage. Here, we present a systematic computational approach that may ultimately be used to unravel protein-protein interactions and molecular mimicry processes that have not yet been solved experimentally. Toward this end, we validate this approach by replicating a set of pre-existing experimental findings that document the structural and functional similarities shared by the human cytomegalovirus-encoded UL144 glycoprotein and human tumor necrosis factor receptor superfamily member 14 (TNFRSF14). We began with a thorough exploration of the Homo sapiens protein database using the Basic Local Alignment Search Tool (BLASTx) to identify proteins sharing sequence homology with UL144. Subsequently, we used AlphaFold2 to predict the independent three-dimensional structures of UL144 and TNFRSF14. This was followed by a comprehensive structural comparison facilitated by Distance-Matrix Alignment and Foldseek. Finally, we used AlphaFold-multimer and PPIscreenML to elucidate potential protein complexes and confirm the predicted binding activities of both UL144 and TNFRSF14. We then used our in silico approach to replicate the experimental finding that revealed TNFRSF14 binding to both B- and T-lymphocyte attenuator (BTLA) and glycoprotein domain and UL144 binding to BTLA alone. This computational framework offers promise in identifying structural similarities and interactions between pathogen-encoded proteins and their host counterparts. This information will provide valuable insights into the cognitive mechanisms underlying the neuropsychiatric effects of viral infections.

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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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