Interactions of hyaladhedrins with hyaluronan and its neutral analog

Kód výsledku v IS VaVaI

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Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Interactions of hyaladhedrins with hyaluronan and its neutral analog

Popis výsledku v původním jazyce

Hyaluronic acid (HA, hyaluronan), an alternating co-polymer of glucuronic acid and N-acetylglucosamine ([4)-β-D-GlcpA-(13)-β-D-GlcpNAc-(1]n), is a major component of extracellular matrix of animal connective tissues. It plays various roles in signaling cascades and is thus involved in inflammation, progression of various diseases including cancer, and wound healing. HA-binding proteins, hyaladherins, which serve as mediators of these processes, are both membrane-bound (CD44, LYVE-1, RHAMM) or soluble (TSG-6). TSG-6 structure is known from numerous NMR experiments that indicate its interaction with HA, heparin and chondroitinsulfate [1]. We applied molecular-dynamics simulations to study the binding of HA oligosaccharides by TSG-6. Two binding sites were identified, one of which is identical with the HA-binding site described previously [2], but the other one, so far unknown, partially overlaps with the binding site of heparin [3] and also for chondroitinsulfate [1]. The specificity of the binding sites for HA and charged oligosaccharides in general was investigated by the comparison of HA with its neutral HA analog containing the glucuronic acid residue instead of glucose [4]. This molecule can be bound by both these sites, but the Helmholtz energies of complex dissociation determined by the umbrella sampling method show a remarkably lower stabilization of the analog in the first site, while in the other site the analog binding is even more stable than that of HA. The second binding site is thus less HA-specific and is able of binding various oligosaccharides independently of their negative charge. It indicates the possibility of designing artificial ligands of hyaladherins with a potential pharmaceutical application.

Název v anglickém jazyce

Interactions of hyaladhedrins with hyaluronan and its neutral analog

Popis výsledku anglicky

Hyaluronic acid (HA, hyaluronan), an alternating co-polymer of glucuronic acid and N-acetylglucosamine ([4)-β-D-GlcpA-(13)-β-D-GlcpNAc-(1]n), is a major component of extracellular matrix of animal connective tissues. It plays various roles in signaling cascades and is thus involved in inflammation, progression of various diseases including cancer, and wound healing. HA-binding proteins, hyaladherins, which serve as mediators of these processes, are both membrane-bound (CD44, LYVE-1, RHAMM) or soluble (TSG-6). TSG-6 structure is known from numerous NMR experiments that indicate its interaction with HA, heparin and chondroitinsulfate [1]. We applied molecular-dynamics simulations to study the binding of HA oligosaccharides by TSG-6. Two binding sites were identified, one of which is identical with the HA-binding site described previously [2], but the other one, so far unknown, partially overlaps with the binding site of heparin [3] and also for chondroitinsulfate [1]. The specificity of the binding sites for HA and charged oligosaccharides in general was investigated by the comparison of HA with its neutral HA analog containing the glucuronic acid residue instead of glucose [4]. This molecule can be bound by both these sites, but the Helmholtz energies of complex dissociation determined by the umbrella sampling method show a remarkably lower stabilization of the analog in the first site, while in the other site the analog binding is even more stable than that of HA. The second binding site is thus less HA-specific and is able of binding various oligosaccharides independently of their negative charge. It indicates the possibility of designing artificial ligands of hyaladherins with a potential pharmaceutical application.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10610 - Biophysics

Projekt

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Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů