Mutually exclusive locales for N-linked glycans and disorder in human glycoproteins

Abstract

Several post-translational protein modifications lie predominantly within regions of disorder: the biased localization has been proposed to expand the binding versatility of disordered regions. However, investigating a representative dataset of 500 human N-glycoproteins, we observed the sites of n-linked glycosylations or n-glycosites, to be predominantly present in the regions of predicted order. When compared with disordered stretches, ordered regions were not found to be enriched for asparagines, serines and threonines, residues that constitute the sequon signature for conjugation of N-glycans. We then investigated the basis of mutual exclusivity between disorder and N-glycosites on the basis of amino acid distribution: when compared with control ordered residue stretches without any N-glycosites, residue neighborhoods surrounding N-glycosites showed a depletion of bulky, hydrophobic and disorder-promoting amino acids and an enrichment for flexible and accessible residues that are frequently found in coiled structures. When compared with control disordered residue stretches without any N-glycosites, N-glycosite neighborhoods were depleted of charged, polar, hydrophobic and flexible residues and enriched for aromatic, accessible and order-promoting residues with a tendency to be part of coiled and β structures. N-glycosite neighborhoods also showed greater phylogenetic conservation among amniotes, compared with control ordered regions, which in turn were more conserved than disordered control regions. our results lead us to propose that unique primary structural compositions and differential propensities for evolvability allowed for the mutual spatial exclusion of n-glycosite neighborhoods and disordered stretches.One of the common co-and post-translational modifications of polypeptides is the conjugation of branched glycosylations to asparagines (known as N-linked glycosylations) 1 . N-linked glycosylation begins with the assembly of an oligosaccharide on dolichol pyrophosphate and the subsequent transfer of the oligosaccharide to the asparagine residues of polypeptides in the lumen of the endoplasmic reticulum; the oligosaccharide is further remodeled in the Golgi complex. Several proteins that end up in the extracellular milieu or as transmembrane proteins are N-linked glycoconjugates. The establishment of organismal morphologies has been sought to be understood through the interactions of a highly conserved set of proteins known as the developmental genetic toolkit 2 . Most toolkit proteins, which are involved in tissue-scale processes, such as cell-cell and cell-matrix adhesion, diffusion-driven signaling and cell movement, are extracellular-or membrane-bound glycoproteins 3,4 . The fundamental role of such toolkit proteins in mechanisms of organ-and organismal-development across diverse clades suggests evolutionary constraints on their structures and folds, while they may have continued to evolve to perform newer functions as organisms occupied and constructed newer niches.A large number of eukaryotic pro...

Systems-wide analysis of glycoprotein conformational changes by limited deglycosylation assay

“…Analysis of ordered and disordered localization of the Nglycosite using ODiNPred showed that at position N37, the probability of the N-glycosite to be located in a disordered region was 0.0342 (Figure 4D). All N37 neighbouring amino acid residues had low probabilities of disorder, in agreement with findings on N-glycosites of human proteins [94]. (Q86SR1/ GALNT10) at positions N124, N146 and N593 [95], glycosites also conserved in M. mulatta GALNT10.…”

Systems-wide analysis of glycoprotein conformational changes by limited deglycosylation assay

“…Analysis of ordered and disordered localization of the Nglycosite using ODiNPred showed that at position N37, the probability of the N-glycosite to be located in a disordered region was 0.0342 (Figure 4D). All N37 neighbouring amino acid residues had low probabilities of disorder, in agreement with findings on N-glycosites of human proteins [94]. Two of the proteins identified in subset iii) included proteins involved in the protein glycosylation machinery; hexosyltransferase (F6UCJ0/ B3GALNT1) and polypeptide Nacetylgalactosaminyltransferase (A0A1D5QY41/GALNT10).…”

“…Thermodynamic and experimental analyses have shown that N-glycosylation often stabilize the glycoprotein structure [109,110]. N-glycosites are found mainly in ordered regions; amino acid residues surrounding Nsequons are relatively poor in hydrophobic and bulky residues known to promote disordered regions [94]. Proteome-wide structural analysis of N-glycosites from human, mouse, fly, plant and yeast showed that a high proportion of N-glycosites are localized within a turn/loop and are solventexposed [111][112][113].…”

Optical Response of Sila-Fulleranes in Interaction With Glycoproteins for Environmental Monitoring

“…Glycoprotein is a combination of protein and carbohydrate. There are different types of glycoproteins, however, the most common glycoproteins that make virus spikes, like the spike of the coronaviruses, are O-Link and N-Link types [39][40][41][42][43]. If the causative of carbohydrate-binding to protein is oxygen atoms, it is called O-Link, and if it is nitrogen atoms, it is called N-Link.…”