Deciphering the molecular basis of the specificity of protein-carbohydrate interactions by statistical analysis of 3D structural data from the Protein Data Bank

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RojasMaciasMiguel_2015_05_05.pdf (8.66 MB)

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2014

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DOI:
http://dx.doi.org/10.22029/jlupub-10365

Abstract

Glycoproteins, proteins with covalently attached sugar residues, are commonly found on the surface of almost all cells where they give rise to a vast layer called glycocalyx. The intricacy of this layer confers cells with a distinctive identity that is recognized by proteins and other receptors. Such protein-carbohydrate interactions set the basis for a broad range of essential biological events, including cell adhesion, signal transduction, the migration of leukocytes to sites of inflammation and the immunological response to carbohydrate antigens. Therefore, the need to comprehend these interactions in detail.Carbohydrate-binding proteins show a remarkable specificity, being able to discern between very similar glycan residues. In order to better understand this precise specificity, the spatial vicinity of common monosaccharide residues is inspected in order to determine their amino acid preferences. Two datasets have been examined. Firstly, one composed of non-covalently bound carbohydrates ligands. The results of this analysis is compared to the second dataset, obtained from the study of the spatial vicinity of the monosaccharides that form the common structural core shared by different types of N-glycans. Amino acid patterns were determined based on two measures: absolute numbers and deviations from natural abundances. Superimposition of protein atoms made possible to display in more detail how interactions are established based on their stereochemical structure. This study is not limited to a given protein-carbohydrate complex, instead, all 3D structures of protein-carbohydrate complexes found in the Protein Data Bank are collected, clustered, and statistically analyzed.The results show that polar amino acids are more frequently found in the vicinity of the analyzed monosaccharides than non-polar residues. Due to the hydrophilic nature of glycan residues, it is not surprising that the main force directing protein-carbohydrate interactions is hydrogen bonding. However, contacts between sugar residues and the non-polar surfaces of aromatic amino acids are confirmed to be also essential for the discrimination of carbohydrate residues. The role of Trp is especially remarkable since it is clearly overrepresented around all analyzed carbohydrate residues. Monosaccharides display polar and non-polar patches on their surfaces that define the way in which interactions with proteins are established. Accordingly, changes in their conformations may also change the pattern of these patches and affect binding specificity. Linkages between proteins and glycans also influence the distribution of amino acids. For example, when comparing amino acids found in the spatial vicinity of N-glycans with those surrounding the glycosylation site, it is shown that the N-glycans interact mostly with amino acids located far from the glycosylation site. This suggests that N-glycans have a minor role at building a binding site, in contrast to non-covalently bound ligands.This study proves that the Protein Data Bank can be effectively used as indirect source of carbohydrate 3D data. The results constitute a guide on the type of amino acid preferences that each of the analyzed monosaccharides display. The statistical analysis was performed with a bioinformatics application that was redeveloped for this purpose. This software is publicly accessible, and different parameters can be used to refine the search space. Even if the number of entries is small, in some cases the results are interesting since they indicate the beginning of a pattern which can be later corroborated once the number of entries increases.

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