Structure-based Comparative Analysis and Prediction of N-linked Glycosylation Sites in Evolutionarily Distant Eukaryotes

• Published in: Genomics, proteomics & bioinformatics Vol. 11; no. 2; pp. 96 - 104
• Main Authors: Lam, Phuc Vinh Nguyen, Goldman, Radoslav, Karagiannis, Konstantinos, Narsule, Tejas, Simonyan, Vahan, Soika, Valerii, Mazumder, Raja
• Format: Journal Article
• Language: English
• Published: China Elsevier Ltd 01.04.2013; Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA%Department of Oncology, Georgetown University, Washington, DC 20057, USA%Department of Biochemistry and Molecular Biology, George Washington University Medical Center, Washington, DC 20037, USA%Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, MD 20852, USA; Life Sciences Department, Paris Diderot University, Paris 75013, France; Elsevier
• Subjects: Amino Acid Motifs; Amino Acids - metabolism; Animals; Arabidopsis; Arabidopsis Proteins - metabolism; Arabidopsis thaliana; Artificial Intelligence; Asparagine - metabolism; BASIC BIOLOGICAL SCIENCES; Biological Evolution; crystal structure; Databases, Protein; Drosophila melanogaster; Drosophila Proteins - metabolism; Eukaryota; eukaryotic cells; Gain and loss of glycosylation; glycoproteins; Glycoproteins - genetics; Glycoproteins - metabolism; Glycosylation; Humans; Mice; Mus musculus; N-linked glycosylation; N-糖基化; nsSNP; nsSNV; Original Research; Polymorphism, Single Nucleotide; prediction; proline; Protein Processing, Post-Translational; Proteome; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins - metabolism; Software; Variation; 分析工具; 生物进化; 真核; 结构比较; 结构预测; 蛋白质构象; 连接; Gain and loss of glycosylation; nsSNP; N-linked glycosylation; Variation; nsSNV
• ISSN: 1672-0229; 2210-3244
• DOI: 10.1016/j.gpb.2012.11.003

The asparagine-X-serine/threonine (NXS/T) motif, where X is any amino acid except proline, is the consensus motif for N-linked glycosylation. Significant numbers of high-resolution crystal structures of glycosylated proteins allow us to carry out structural analysis of the N-linked glycosylation sites (NGS). Our analysis shows that there is enough structural information from diverse glycoproteins to allow the development of rules which can be used to predict NGS. A Python-based tool was developed to investigate asparagines implicated in N-glycosylation in five species: Homo sapiens, Mus musculus, Drosophila melanogaster, Arabidopsis thaliana and Saccharomyces cerevisiae. Our analysis shows that 78% of all asparagines of NXS/T motif involved in N-glycosylation are localized in the loop/turn conformation in the human proteome. Similar distribution was revealed for all the other species examined. Comparative analysis of the occurrence of NXS/T motifs not known to be glycosylated and their reverse sequence (S/TXN) shows a similar distribution across the secondary structural elements, indicating that the NXS/T motif in itself is not biologically relevant. Based on our analysis, we have defined rules to determine NGS. Using machine learning methods based on these rules we can predict with 93% accuracy if a particular site will be glycosylated. If structural information is not available the tool uses structural prediction results resulting in 74% accuracy. The tool was used to identify glycosylation sites in 108 human proteins with structures and 2247 proteins without structures that have acquired NXS/T site/s due to non-synonymous variation. The tool, Structure Feature Analysis Tool (SFAT), is freely available to the public at http://hive.biochemistry.gwu.edu/tools/sfat.