Charge and Polarity Preferences for N-Glycosylation: A Genome-Wide In Silico Study and Its Implications Regarding Constitutive Proliferation and Adhesion of Carcinoma Cells.

Muhammad Ramzan Manwar Hussain,Wajahat M Qazi,Zeeshan Iqbal,Daniel C Hoessli

doi:10.3389/fonc.2018.00029

Abstract

The structural and functional diversity of the human proteome is mediated by N- and O-linked glycosylations that define the individual properties of extracellular and membrane-associated proteins. In this study, we utilized different computational tools to perform in silico based genome-wide mapping of 1,117 human proteins and unravel the contribution of both penultimate and vicinal amino acids for the asparagine-based, site-specific N-glycosylation. Our results correlate the non-canonical involvement of charge and polarity environment of classified amino acids (designated as L, O, A, P, and N groups) in the N-glycosylation process, as validated by NetNGlyc predictions, and 130 literature-reported human proteins. From our results, particular charge and polarity combinations of non-polar aliphatic, acidic, basic, and aromatic polar side chain environment of both penultimate and vicinal amino acids were found to promote the N-glycosylation process. However, the alteration in side-chain charge and polarity environment of genetic variants, particularly in the vicinity of Asn-containing epitope, may induce constitutive glycosylation (e.g., aberrant glycosylation at preferred and non-preferred sites) of membrane proteins causing constitutive proliferation and triggering epithelial-to-mesenchymal transition. The current genome-wide mapping of 1,117 proteins (2,909 asparagine residues) was used to explore charge- and polarity-based mechanistic constraints in N-glycosylation, and discuss alterations of the neoplastic phenotype that can be ascribed to N-glycosylation at preferred and non-preferred sites.

Highlights

Glycosylation of proteins is a most complex form of co- and post-translational modifications introducing structural diversity to proteins in the form of O- and N- linked sugar moieties [1,2,3,4,5,6,7,8]
Proteins that undergo N-linked glycosylation are biosynthesized on membrane-associated ribosomes and their signal peptide is removed by a signal peptidase as they emerge into the lumen of the rough endoplasmic reticulum
The rapid increase of substrate data for protein N-glycosylation has led to the development of different databases and prediction tools: dbPTMs, UniProt, NetNGlyc and MAPRes (Mining Association Patterns among preferred amino acid residues in the vicinity of amino acids targeted for post-translational modifications) [10, 12,13,14,15]

Summary

Introduction

Glycosylation of proteins is a most complex form of co- and post-translational modifications introducing structural diversity to proteins in the form of O- and N- linked sugar moieties [1,2,3,4,5,6,7,8]. Proteins that undergo N-linked glycosylation are biosynthesized on membrane-associated ribosomes and their signal peptide is removed by a signal peptidase as they emerge into the lumen of the rough endoplasmic reticulum. The rapid increase of substrate data for protein N-glycosylation has led to the development of different databases and prediction tools: dbPTMs, UniProt, NetNGlyc and MAPRes (Mining Association Patterns among preferred amino acid residues in the vicinity of amino acids targeted for post-translational modifications) [10, 12,13,14,15]

Methods

Results

Discussion

Conclusion