Titre :

Molecular dynamics simulations shed light into the donor substrate specificity of vertebrate poly-alpha-2,8-sialyltransferases ST8Sia IV

Auteur(s) :

Teppa, Elin [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576
Galuska, Sebastian Peter [Auteur]
Leibniz Institute for Farm Animal Biology [FBN]
Harduin-Lepers, Anne [Auteur]
Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Titre de la revue :

Biochimica et Biophysica Acta (BBA) - General Subjects

Numéro :

1868

Pagination :

130647

Éditeur :

Elsevier

Date de publication :

2024-08

ISSN :

0304-4165

Mot(s)-clé(s) en anglais :

Sialyltransferases
Sugar donor
Polysialyltransferases
Substrate specificity
Structure
Molecular dynamics
Modeling

Discipline(s) HAL :

Sciences du Vivant [q-bio]
Chimie/Chimie théorique et/ou physique

Résumé en anglais : [en]

Background Sialic acids are essential monosaccharides influencing several biological processes and disease states. The sialyltransferases catalyze the transfer of Sia residues to glycoconjugates playing critical roles ...
Lire la suite >Background Sialic acids are essential monosaccharides influencing several biological processes and disease states. The sialyltransferases catalyze the transfer of Sia residues to glycoconjugates playing critical roles in cellular recognition and signaling. Despite their importance, the molecular mechanisms underlying their substrate specificity, especially between different organisms, remain poorly understood. Recently, the human ST8Sia IV, a key enzyme in the synthesis of polysialic acids, was found to accept only CMP-Neu5Ac as a sugar-donor, whereas the whitefish Coregonus maraena enzyme showed a wider donor substrate specificity, accepting CMP-Neu5Ac, CMP-Neu5Gc, and CMP-Kdn. However, what causes these differences in donor substrate specificity is unknown. Methods Computational approaches were used to investigate the structural and biochemical determinants of the donor substrate specificity in ST8Sia IV. Accurate structural models of the human and fish ST8Sia IV catalytic domains and their complexes with three sialic acid donors (CMP-Neu5Ac, CMP-Neu5Gc, and CMP-Kdn) were generated. Subsequently, molecular dynamics simulations were conducted to analyze the stability and interactions within these complexes and identify differences in complex stability and substrate binding sites between the two ST8Sia IV. Results Our MD simulations revealed that the human enzyme effectively stabilizes CMP-Neu5Ac, whereas CMP-Neu5Gc and CMP-Kdn are unstable and explore different conformations. In contrast, the fish ST8Sia IV stabilizes all three donor substrates. Based on these data, we identified the key interacting residues for the different Sias parts of the substrate donors. General significance This work advances our knowledge of the enzymatic mechanisms governing sialic acid transfer, shedding light on the evolutionary adaptations of sialyltransferases.Lire moins >

Langue :

Anglais

Audience :

Internationale

Vulgarisation :

Non

Projet ANR :

Des polysialyltransférases d'origine marine pour la synthèse de bioconjugués immunomodulateurs

Établissement(s) :

Université de Lille
CNRS

Collections :

• Unité de Glycobiologie Structurale et Fonctionnelle (UGSF) - UMR 8576

Équipe(s) de recherche :

Régulation de la glycosylation terminale

Date de dépôt :

2024-06-19T09:43:12Z
2024-06-26T08:44:18Z
2024-08-22T07:54:42Z