Implications of Heparan Sulfate and Heparanase in Amyloid Diseases

Li, Jinping; Zhang, Xiao

doi:10.1007/978-3-030-34521-1_25

Cited by 9 publications

(8 citation statements)

References 63 publications

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“…CS has been found to have major roles in neurobiology [ 9 , 12 , 13 , 14 ]. Although oligosaccharide sequences with high selectivity for target proteins have yet to be identified, CS-E (GalNAc4S6S) has been found to be a powerful neuronal modulator [ 2 , 15 , 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Their roles in the modulation of neuronal functions are particularly intriguing and exciting. On the pathological side, GAGs have been shown to play a role in Alzheimer’s disease, tauopathies, and amyloid diseases [ 12 , 13 ]. A key member of the GAG superfamily is chondroitin sulfate (CS), which is present in the brain and has been associated with neuronal development and dysfunction [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism

2022

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GAGs exhibit a high level of conformational and configurational diversity, which remains untapped in terms of the recognition and modulation of proteins. Although GAGs are suggested to bind to more than 800 biologically important proteins, very few therapeutics have been designed or discovered so far. A key challenge is the inability to identify, understand and predict distinct topologies accessed by GAGs, which may help design novel protein-binding GAG sequences. Recent studies on chondroitin sulfate (CS), a key member of the GAG family, pinpointing its role in multiple biological functions led us to study the conformational dynamism of CS building blocks using molecular dynamics (MD). In the present study, we used the all-atom GLYCAM06 force field for the first time to explore the conformational space of all possible CS building blocks. Each of the 16 disaccharides was solvated in a TIP3P water box with an appropriate number of counter ions followed by equilibration and a production run. We analyzed the MD trajectories for torsional space, inter- and intra-molecular H-bonding, bridging water, conformational spread and energy landscapes. An in-house phi and psi probability density analysis showed that 1→3-linked sequences were more flexible than 1→4-linked sequences. More specifically, phi and psi regions for 1→4-linked sequences were held within a narrower range because of intra-molecular H-bonding between the GalNAc O5 atom and GlcA O3 atom, irrespective of sulfation pattern. In contrast, no such intra-molecular interaction arose for 1→3-linked sequences. Further, the stability of 1→4-linked sequences also arose from inter-molecular interactions involving bridged water molecules. The energy landscape for both classes of CS disaccharides demonstrated increased ruggedness as the level of sulfation increased. The results show that CS building blocks present distinct conformational dynamism that offers the high possibility of unique electrostatic surfaces for protein recognition. The fundamental results presented here will support the development of algorithms that help to design longer CS chains for protein recognition.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism

2022

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“…Ubiquitously expressed on the cell surface and ECM of all cell types, HSPGs regulate numerous signaling pathways involved in developmental and physiopathological processes [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Beside an important structural role, HSPGs—through either their negatively charged sulfated moieties of HS chains or the protein cores—interact with a variety of ligands regulating their distribution, availability, and signaling activity.…”

Section: Heparan Sulfate Proteoglycans: Structure Biosynthesis Processing and Functionsmentioning

confidence: 99%

“…Beside an important structural role, HSPGs—through either their negatively charged sulfated moieties of HS chains or the protein cores—interact with a variety of ligands regulating their distribution, availability, and signaling activity. Hence, HSPGs play fundamental roles in cell proliferation, differentiation, adhesion, migration, survival, autophagy, inflammation, immune defense, and many other cellular processes [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. HSPGs serve as co-receptors for morphogens and growth factors, allowing a proper presentation to their cognate receptors, either in cis (on the same cell) or in trans (on adjacent cells), thus facilitating receptor activation and downstream signaling [ 1 , 2 , 3 , 4 , 9 , 14 , 15 , 18 , 19 , 20 ].…”

Section: Heparan Sulfate Proteoglycans: Structure Biosynthesis Processing and Functionsmentioning

confidence: 99%

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Pasquale

Quiccione

Tafuri

et al. 2021

IJMS

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Heparan sulfate proteoglycans (HSPGs) encompass a group of glycoproteins composed of unbranched negatively charged heparan sulfate (HS) chains covalently attached to a core protein. The complex HSPG biosynthetic machinery generates an extraordinary structural variety of HS chains that enable them to bind a plethora of ligands, including growth factors, morphogens, cytokines, chemokines, enzymes, matrix proteins, and bacterial and viral pathogens. These interactions translate into key regulatory activity of HSPGs on a wide range of cellular processes such as receptor activation and signaling, cytoskeleton assembly, extracellular matrix remodeling, endocytosis, cell-cell crosstalk, and others. Due to their ubiquitous expression within tissues and their large functional repertoire, HSPGs are involved in many physiopathological processes; thus, they have emerged as valuable targets for the therapy of many human diseases. Among their functions, HSPGs assist many viruses in invading host cells at various steps of their life cycle. Viruses utilize HSPGs for the attachment to the host cell, internalization, intracellular trafficking, egress, and spread. Recently, HSPG involvement in the pathogenesis of SARS-CoV-2 infection has been established. Here, we summarize the current knowledge on the molecular mechanisms underlying HSPG/SARS-CoV-2 interaction and downstream effects, and we provide an overview of the HSPG-based therapeutic strategies that could be used to combat such a fearsome virus.

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“…This tremendous functional versatility is associated with the structural complexity of HS, whose composition was shown to depend on the cell type and developmental stage 8 . Malfunctioning of HS biosynthesis, on the other hand, has been linked to an increased susceptibility to Alzheimer's disease, inflammation, viral infections and tumorigenesis [9][10][11][12] .…”

Section: Introductionmentioning

confidence: 99%

Structure of the human heparan sulfate polymerase complex EXT1-EXT2

Leisico

Omeiri

Narvor

et al. 2022

Preprint

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Heparan sulfates are complex polysaccharides that mediate the interaction with a broad range of protein ligands at the cell surface. A key step in heparan sulfate biosynthesis is catalyzed by the bi-functional glycosyltransferases EXT1 and EXT2, which generate the glycan backbone consisting of repeating N-acetylglucosamine and glucuronic acid units. The molecular mechanism of heparan sulfate chain polymerization remains, however, unknown. Here, we present the cryo-electron microscopy structure of human EXT1-EXT2, which reveals the formation of a tightly packed hetero-dimeric complex harboring four glycosyltransferase domains with their catalytic sites facing in opposite directions. Along with in vitro activity assays using fluorescently labeled and chemically defined substrates, these findings provide a molecular insight into donor substrate recognition and demonstrate that the glycosyltransferase reactions are highly specific. A combination of in vitro and in cellulo mutational studies was used to dissect the functional role of the four catalytic sites. While EXT1 is able to catalyze both glycosyltransferase reactions, EXT2 harbors only N-acetylglucosamine transferase activity. Our results provide mechanistic insight into heparan sulfate chain elongation as a non processive process and lay the cornerstone for future studies on EXT1-EXT2 function in health and disease.

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Implications of Heparan Sulfate and Heparanase in Amyloid Diseases

Cited by 9 publications

References 63 publications

In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism

In-Depth Molecular Dynamics Study of All Possible Chondroitin Sulfate Disaccharides Reveals Key Insight into Structural Heterogeneity and Dynamism

Heparan Sulfate Proteoglycans in Viral Infection and Treatment: A Special Focus on SARS-CoV-2

Structure of the human heparan sulfate polymerase complex EXT1-EXT2

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