Functional repertoire, molecular pathways and diseases associated with 3D domain swapping in the human proteome.

Khader Shameer, Ramanathan Sowdhamini
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引用次数: 11

Abstract

Unlabelled:

Background: 3D domain swapping is a novel structural phenomenon observed in diverse set of protein structures in oligomeric conformations. A distinct structural feature, where structural segments in a protein dimer or higher oligomer were shared between two or more chains of a protein structure, characterizes 3D domain swapping. 3D domain swapping was observed as a key mediator of numerous functional mechanisms and play pathogenic role in various diseases including conformational diseases like amyloidosis, Alzheimer's disease, Parkinson's disease and prion diseases. We report the first study with a focus on identifying functional classes, pathways and diseases mediated by 3D domain swapping in the human proteome.

Methods: We used a panel of four enrichment tools with two different ontologies and two annotations database to derive biological and clinical relevant information associated with 3D domain swapping. Protein domain enrichment analysis followed by Gene Ontology (GO) term enrichment analysis revealed the functional repertoire of proteins involved in swapping. Pathway analysis using KEGG annotations revealed diverse pathway associations of human proteins involved in 3D domain swapping. Disease Ontology was used to find statistically significant associations with proteins in swapped conformation and various disease categories (P-value < 0.05).

Results: We report meta-analysis results of a literature-curated dataset of human gene products involved in 3D domain swapping and discuss new insights about the functional repertoire, pathway associations and disease implications of proteins involved in 3D domain swapping.

Conclusions: Our integrated bioinformatics pipeline comprising of four different enrichment tools, two ontologies and two annotations revealed new insights into the functional and disease correlations with 3D domain swapping. GO term enrichment were used to infer terms associated with three different GO categories. Protein domain enrichment was used to identify conserved domains enriched in swapped proteins. Pathway enrichment analysis using KEGG annotations revealed that proteins with swapped conformations are present in all six classes of KEGG BRITE hierarchy and significantly enriched KEGG pathways were observed in five classes. Five major classes of disease were found to be associated with 3D domain swapping using functional disease ontology based enrichment analysis. Five classes of human diseases: cancer, diseases of the respiratory or pulmonary system, degenerative diseases of the central nervous system, vascular disease and encephalitis were found to be significant. In conclusion, our study shows that bioinformatics based analytical approaches using curated data can enhance the understanding of functional and disease implications of 3D domain swapping.

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与人类蛋白质组三维结构域交换相关的功能库、分子途径和疾病。
背景:三维结构域交换是一种新的结构现象,在不同的低聚构象的蛋白质结构中观察到。一种独特的结构特征,即蛋白质二聚体或更高的低聚物的结构片段在蛋白质结构的两条或多条链之间共享,表征了3D结构域交换。三维结构域交换是多种功能机制的关键中介,在淀粉样变性、阿尔茨海默病、帕金森病和朊病毒病等构象疾病中起着重要的致病作用。我们报告了第一项研究,重点是识别人类蛋白质组中3D结构域交换介导的功能类别、途径和疾病。方法:我们使用了四种不同本体的浓缩工具和两个注释数据库,以获得与三维域交换相关的生物学和临床相关信息。蛋白质结构域富集分析和基因本体(GO)项富集分析揭示了参与交换的蛋白质的功能库。使用KEGG注释的途径分析揭示了参与三维结构域交换的人类蛋白质的多种途径关联。使用疾病本体(Disease Ontology)发现交换构象蛋白与各种疾病类别之间存在统计学意义上的关联(p值< 0.05)。结果:我们报告了涉及3D结构域交换的人类基因产物文献整理数据集的荟萃分析结果,并讨论了涉及3D结构域交换的蛋白质的功能库、途径关联和疾病含义的新见解。结论:我们的集成生物信息学管道包括四种不同的富集工具,两种本体和两种注释,揭示了与3D结构域交换的功能和疾病相关性的新见解。氧化石墨烯术语富集用于推断与三种不同氧化石墨烯类别相关的术语。蛋白质结构域富集用于鉴定交换蛋白中富集的保守结构域。使用KEGG注释的途径富集分析显示,具有交换构象的蛋白质存在于所有6类KEGG BRITE结构中,并且在5类中观察到显著富集的KEGG通路。利用基于功能疾病本体的富集分析,发现五大类疾病与三维域交换相关。五类人类疾病:癌症、呼吸系统或肺系统疾病、中枢神经系统退行性疾病、血管疾病和脑炎被发现是重要的。总之,我们的研究表明,基于生物信息学的分析方法使用整理的数据可以增强对三维结构域交换的功能和疾病影响的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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