The impact of<i>O</i>-glycan chemistry on the stability of intrinsically disordered proteins

Prates, Érica T.; Guan, Xiaoyu; Li, Yaohao; Wang, Xinfeng; Chaffey, Patrick K.; Skaf, Munir S.; Crowley, Michael F.; Beckham, Gregg T.

doi:10.1039/c7sc05016j

Cited by 23 publications

(26 citation statements)

References 35 publications

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“…Proline also follow the same pattern as glycine, however, its abundance may be due to the presence of pyrrolidine ring which contain imino group present in its side chain, which allows it to introduce kinks or turns in the protein structure. It is well known that high proline content is generally found in disordered proteins {Prates, 2018 #60}. Our results from this study lead us to propose that a spatial separation between sites of N-glycosites and protein disordered region sites potentially acts as a constraint to distinguish residue stretches that contribute to protein structure and function.…”

Section: Discussionsupporting

confidence: 57%

“…In addition to phosphorylation, O-linked glycosylations have also been predicted to inhabit the disordered regions of proteins (Nishikawa et al, 2010). It is reported that the evolutionary selection favored the resistance to proteolysis by coevolution of protein sequence with the site of O-glycosylation (Prates et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In fact, intermediate steps in the biosynthesis of N-linked glycans act as checkpoints to ensure only correctly folded proteins traffic along the ER-Golgi axis (Ferris et al, 2014). Thermodynamic and molecular dynamics studies show that N-linked an O-linked glycans enhance the stability of the tertiary structure of proteins { Tams, 1998 #12; Shental-Bechor, 2008 #21; Prates, 2018 #60}. Keeping the above observations in mind, we asked whether the sites of N-glycosylations showed any bias in their locations vis-a-vis the (dis)ordered regions of N-linked glycoproteins.…”

Section: Introductionmentioning

confidence: 99%

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

Singh

Kumari

Pally

et al. 2018

Preprint

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6Several post-translational modifications of proteins lie within regions of disorder, stretches of 7 amino acid residues that exhibit a dynamic tertiary structure and resist crystallization. Such 8 localization has been proposed to expand the binding versatility of the disordered regions, and 9 hence, the repertoire of interacting partners for the proteins. However, investigating a dataset of 1 0 500 human N-linked glycoproteins, we observed that the sites of N-linked glycosylations, or N-1 1 glycosites, lay predominantly within the regions of predicted order rather than their unstructured 1 2 counterparts. This mutual exclusivity between disordered stretches and N-glycosites could not be 1 3 reconciled merely through asymmetry in distribution of asparagines, serines or threonines 1 4 residues, which comprise the minimum-required signature for conjugation by N-linked glycans, 1 5but rather by a contextual enrichment of these residues next to each other within the ordered 1 6 portions. In fact, N-glycosite neighborhoods and disordered stretches showed distinct sets of 1 7 enriched residues suggesting their individualized roles in protein phenotype. N-glycosite 1 8 neighborhood residues also showed higher phylogenetic conservation than disordered stretches 1 9

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Singh

Kumari

Pally

et al. 2018

Preprint

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“…The abundance of pyrrolidine ring-containing proline allows it to introduce kinks or turns in the protein structure and contributes to its propensity within interdomain linkers. It is well known that proline content is generally higher within disordered stretches 22 . Therefore, N-glycosite neighborhoods are uniquely placed in terms of their biochemical properties separating them from the hydrophobic ordered core and the disordered stretches of N-linked glycoproteins.…”

Section: Discussionmentioning

confidence: 99%

“…Intermediate steps in N-glycan biosynthesis act as checkpoints to ensure that only correctly folded proteins traffic along the ER-Golgi axis 24 . Thermodynamic and molecular dynamics studies show that glycans enhance the stability of the tertiary structure of proteins 22,25,26 . Keeping the above observations in mind, we asked whether the sites of N-glycan conjugation (N-glycosites) showed any bias in their locations vis-a-vis (dis)ordered regions of N-glycoproteins.…”

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confidence: 99%

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

Goutham¹,

Kumari

Pally³

et al. 2020

Sci Rep

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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...

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Just a spoonful of sugar: Short glycans affect protein properties and functions

Bello

Rovero

Papini

2019

Journal of Peptide Science

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Glycosylation has a strong impact on the chemical and physical properties of proteins and on their activity. The heterogeneous nature of this modification complicates the elucidation of the role of each glycan, thus slowing down the progress in glycobiology. Nevertheless, the great advances recently made in protein engineering and in the chemical synthesis, and semisynthesis of glycoproteins are giving impulse to the field, fostering important discoveries. In this review, we report on the findings of the last two decades on the importance that the attachment site, linkage, and composition of short glycans have in affecting protein properties and functions.

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The impact ofO-glycan chemistry on the stability of intrinsically disordered proteins

Abstract: Protein glycosylation is a diverse post-translational modification that serves myriad biological functions.

Cited by 23 publications

References 35 publications

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

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

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

Just a spoonful of sugar: Short glycans affect protein properties and functions

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