Hyaluronan and Reactive Oxygen Species Signaling—Novel Cues from the Matrix?

Antioxidants, Год журнала: 2023, Номер 12(4), С. 824 - 824

Опубликована: Март 28, 2023

Hyaluronan (HA) is a naturally occurring non-sulfated glycosaminoglycan (GAG) localized to the cell surface and tissue extracellular matrix (ECM). It composed of disaccharides containing glucuronic acid N-acetylglucosamine, synthesized by HA synthase (HAS) enzymes degraded hyaluronidase (HYAL) or reactive oxygen nitrogen species (ROS/RNS) actions. deposited as high molecular weight (HMW) polymer low (LMW) fragments oligosaccharides. affects biological functions interacting with HA-binding proteins (hyaladherins). HMW anti-inflammatory, immunosuppressive, antiangiogenic, whereas LMW has pro-inflammatory, pro-angiogenetic, oncogenic effects. ROS/RNS degrade HA, albeit at enhanced levels during injury inflammatory processes. Thus, degradation endothelial glycocalyx increased ROS challenges vascular integrity can initiate several disease progressions. Conversely, exerts vital role in wound healing through ROS-mediated modifications, which affect innate immune system. The normal turnover protects against rigidification. Insufficient leads rigidity, leading dysfunction. Both endogenous exogenous have scavenging capacity ROS. interactions are more complex than presently perceived present an important research topic.

Язык: Английский

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A biological guide to glycosaminoglycans: current perspectives and pending questions

FEBS Journal, Год журнала: 2024, Номер 291(15), С. 3331 - 3366

Опубликована: Март 18, 2024

Mammalian glycosaminoglycans (GAGs), except hyaluronan (HA), are sulfated polysaccharides that covalently attached to core proteins form proteoglycans (PGs). This article summarizes key biological findings for the most widespread GAGs, namely HA, chondroitin sulfate/dermatan sulfate (CS/DS), keratan (KS), and heparan (HS). It focuses on major processes remain be deciphered get a comprehensive view of mechanisms mediating GAG functions. They include regulation biosynthesis postsynthetic modifications in heparin (HP) HS, composition, heterogeneity, function tetrasaccharide linkage region its role disease, functional characterization new PGs recently identified by glycoproteomics, selectivity interactions mediated chains, display chains at cell surface their impact availability activity soluble ligands, move through glycocalyx layer reach receptors, human profile health roles GAGs particular (syndecans, decorin, biglycan) involved cancer, inflammation, fibrosis, possible use as disease biomarkers, design inhibitors targeting biosynthetic enzymes GAG-protein develop novel therapeutic approaches.

Язык: Английский

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Restoring Protein Glycosylation with GlycoShape

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Дек. 11, 2023

Abstract During the past few years, we have been witnessing a revolution in structural biology. Leveraging on technological and computational advances, scientists can now resolve biomolecular structures at atomistic level of detail by cryogenic electron microscopy (cryo-EM) predict 3D from sequence alone machine learning (ML). One technique often supports other to provide view atoms molecules required capture function molecular machines. An example extraordinary impact these advances scientific discovery public health is given how information supported rapid development COVID-19 vaccines based SARS-CoV-2 spike (S) glycoprotein. Yet, none new technologies details dense coat glycans covering S, which responsible for its natural, biologically active structure ultimately viral evasion. Indeed, glycosylation, most abundant post-translational modification proteins, largely invisible through experimental biology turn it cannot be reproduced ML, because lack data learn from. Molecular simulations high-performance computing (HPC) fill this crucial gap, yet resources, users’ skills long timescales involved limit applications modelling single study cases. To broaden access glycans, here introduce GlycoShape ( https://glycoshape.org ) an open (OA) glycan database toolbox designed restore glycoproteins their native functional form supplementing available proteins repositories, such as RCSB PDB www.rcsb.org AlphaFold Protein Structure Database https://alphafold.ebi.ac.uk/ ), with missing derived over 1 ms cumulative sampling dynamics (MD) simulations. The Glycan (GDB) currently counts 435 unique principally human glycome additional structures, fragments, epitopes eukaryotic prokaryotic organisms. GDB feeds into Re-Glyco, bespoke algorithm rapidly natural glycosylation protein N- occupancy, where unknown. Ultimately, integration OA databases step-change discovery, characterization biomolecules, all way down pharmacological drug discovery.

Язык: Английский

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Restoring protein glycosylation with GlycoShape

Nature Methods, Год журнала: 2024, Номер 21(11), С. 2117 - 2127

Опубликована: Окт. 14, 2024

Abstract Despite ground-breaking innovations in experimental structural biology and protein structure prediction techniques, capturing the of glycans that functionalize proteins remains a challenge. Here we introduce GlycoShape ( https://glycoshape.org ), an open-access glycan database toolbox designed to restore glycoproteins their native functional form seconds. The counts over 500 unique so far, covering human glycome augmented by elements from wide range organisms, obtained 1 ms cumulative sampling molecular dynamics simulations. These structures can be linked with robust algorithm named Re-Glyco, directly compatible data repositories, such as Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB) AlphaFold Structure Database, or own. quality, performance broad applicability is demonstrated its ability predict N-glycosylation occupancy, scoring 93% agreement experiment, based on screening all PDB corresponding glycoproteomics profile, total 4,259 N - glycosylation sequons.

Язык: Английский

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Benchmarking Water Models in Molecular Dynamics of Protein–Glycosaminoglycan Complexes

Journal of Chemical Information and Modeling, Год журнала: 2024, Номер 64(5), С. 1691 - 1703

Опубликована: Фев. 27, 2024

Glycosaminoglycans (GAGs) made of repeating disaccharide units intricately engage with proteins, playing a crucial role in the spatial organization extracellular matrix (ECM) and transduction biological signals cells to modulate number biochemical processes. Exploring protein-GAG interactions reveals several challenges for their analysis, namely, highly charged periodic nature GAGs, multipose binding, abundance interfacial water molecules complexes. Most studies on are conducted using TIP3P model, there no data effect various models results obtained molecular dynamics (MD) simulations Hence, it is essential perform systematic analysis different MD these systems. In this work, we aim evaluate properties complexes explicit: TIP3P, SPC/E, TIP4P, TIP4PEw, OPC, TIP5P implicit: IGB = 1, 2, 5, 7, 8 find out which them best suited study The FF14SB GLYCAM06 force fields were used proteins respectively. GAG types, such as heparin, chondroitin sulfate, hyaluronic acid basic fibroblast growth factor, cathepsin K, CD44 receptor, respectively, investigated. observed variations descriptors binding emphasize relevance choice simulation

Язык: Английский

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Novel anticancer drug discovery efforts targeting glycosylation: the emergence of fluorinated monosaccharides analogs

Expert Opinion on Drug Discovery, Год журнала: 2025, Номер unknown, С. 1 - 11

Опубликована: Янв. 3, 2025

Introduction Glycosylation is an essential enzymatic process of building glycan structures that occur mainly within the cell and gives rise to a diversity surface secreted glycoconjugates. These glycoconjugates play vital roles, for instance in cellcell adhesion, interaction communication, activation receptors, inflammatory response immune recognition. This controlled wellcoordinated altered cancer, leading biosynthesis cancerassociated glycans, which impact glycandependent biological roles.

Язык: Английский

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Global impact of proteoglycan science on human diseases

iScience, Год журнала: 2023, Номер 26(11), С. 108095 - 108095

Опубликована: Окт. 4, 2023

Язык: Английский

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The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(18), С. 14101 - 14101

Опубликована: Сен. 14, 2023

This review examines the roles of HS-proteoglycans (HS-PGs) in general, and, particular, perlecan and syndecan as representative examples their interactive ligands, which regulate physiological processes cellular behavior health disease. HS-PGs are essential for functional properties tissues both development extracellular matrix (ECM) remodeling that occurs response to trauma or interact with a biodiverse range chemokines, chemokine receptors, protease inhibitors, growth factors immune regulation, inflammation, ECM stabilization, tissue protection. Some cell regulatory proteoglycan receptors dually modified hybrid HS/CS proteoglycans (betaglycan, CD47). Neurexins provide synaptic plasticity, specificity interaction, promoting neurotransduction, neurogenesis, differentiation. Ternary complexes glypican-1 Robbo-Slit neuroregulatory proteins direct axonogenesis neural network formation. Specific neurexin-neuroligin stabilize interactions activity. Disruption these leads neurological deficits disorders cognitive decline. Interactions also promote inhibit tumor development. Thus, have complex diverse normal pathological tissues. Specialized HS-PGs, such neurexins, pikachurin, Eyes-shut, stabilization transduction axenome primary cilium phototoreceptors ribbon synapse bipolar neurons retinal networks, ocular vision. Pikachurin Eyes-Shut an α-dystroglycan photoreceptor synapse. Novel controlling function expected continue be uncovered this fascinating class proteoglycan.

Язык: Английский

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The Landscape of Small Leucine-Rich Proteoglycan Impact on Cancer Pathogenesis with a Focus on Biglycan and Lumican

Cancers, Год журнала: 2023, Номер 15(14), С. 3549 - 3549

Опубликована: Июль 9, 2023

Cancer development is a multifactorial procedure that involves changes in the cell microenvironment and specific modulations functions. A tumor contains cells, non-malignant blood vessels, cells of immune system, stromal extracellular matrix (ECM). The small leucine-rich proteoglycans (SLRPs) are family nineteen proteoglycans, which ubiquitously expressed among mammalian tissues especially abundant ECM. SLRPs divided into five canonical classes (classes I–III, containing fourteen members) non-canonical IV–V, including based on their amino-acid structural sequence, chromosomal organization, functional properties. Variations both protein core structure glycosylation status lead to SLRP-specific interactions with membrane receptors, cytokines, growth factors, ECM molecules. have been implicated regulation cancer growth, motility, invasion, as well cancer-associated inflammation autophagy, highlighting crucial role processes carcinogenesis. Except for class I SLRP decorin, an anti-tumorigenic has attributed, other SLPRs’ roles not fully clarified. This review will focus functions II members biglycan lumican, correlated various aspects development.

Язык: Английский

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Nanosensor based approaches for quantitative detection of heparin

Talanta, Год журнала: 2024, Номер 273, С. 125873 - 125873

Опубликована: Март 4, 2024

Язык: Английский

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