heparitin-sulfate and Protein-Aggregation--Pathological

Highly sulfated domains of heparan sulfate (HS), also known as HS S-domains, consist of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)-]. The expression of HS S-domains at the cell surface is determined by two mechanisms: tightly regulated biosynthetic machinery and enzymatic remodeling by extracellular endoglucosamine 6-sulfatases, Sulf-1 and Sulf-2. Intracellular or extracellular deposits of misfolded and aggregated proteins are characteristic of protein aggregation diseases. Although proteins can aggregate alone, deposits of protein aggregates in vivo contain a number of proteinaceous and non-protein components. HS S-domains are one non-protein component of these aggregated deposits. HS S-domains are considered to be critical for signal transduction of several growth factors and several disease conditions, such as tumor progression, but their roles in protein aggregation diseases are not yet fully understood. This review summarizes the current understanding of the possible roles of HS S-domains and Sulfs in the formation and cytotoxicity of protein aggregates.

Topics: Amyloid; Cell Communication; Heparitin Sulfate; Humans; Protein Aggregates; Protein Aggregation, Pathological; Sulfatases

The global burden of disease caused by a respiratory syncytial virus (RSV) is becoming more widely recognized in young children and adults. Heparan sulfate helps in attaching the virion through G protein with the host cell membrane. In this study, we examined the structural changes of ectodomain G protein (edG) in a wide pH range. The absorbance results revealed that protein maintains its tertiary structure at physiological and highly acidic and alkaline pH. However, visible aggregation of protein was observed in mild acidic pH. The intrinsic fluorescence study shows no significant change in the λ

Topics: Catalytic Domain; Cell Membrane; Heparitin Sulfate; Host-Pathogen Interactions; Humans; Hydrogen Bonding; Hydrogen-Ion Concentration; Molecular Docking Simulation; Protein Aggregates; Protein Aggregation, Pathological; Protein Denaturation; Protein Structure, Tertiary; Respiratory Syncytial Virus, Human; Spectrometry, Fluorescence; Urea; Viral Envelope Proteins

Accumulation of amyloid-β (Aβ) peptide in the brain is the first critical step in the pathogenesis of Alzheimer's disease (AD). Studies in humans suggest that Aβ clearance from the brain is frequently impaired in late-onset AD. Aβ accumulation leads to the formation of Aβ aggregates, which injure synapses and contribute to eventual neurodegeneration. Cell surface heparan sulfates (HSs), expressed on all cell types including neurons, have been implicated in several features in the pathogenesis of AD including its colocalization with amyloid plaques and modulatory role in Aβ aggregation. We show that removal of neuronal HS by conditional deletion of the Ext1 gene, which encodes an essential glycosyltransferase for HS biosynthesis, in postnatal neurons of amyloid model APP/PS1 mice led to a reduction in both Aβ oligomerization and the deposition of amyloid plaques. In vivo microdialysis experiments also detected an accelerated rate of Aβ clearance in the brain interstitial fluid, suggesting that neuronal HS either inhibited or represented an inefficient pathway for Aβ clearance. We found that the amounts of various HS proteoglycans (HSPGs) were increased in postmortem human brain tissues from AD patients, suggesting that this pathway may contribute directly to amyloid pathogenesis. Our findings have implications for AD pathogenesis and provide insight into therapeutic interventions targeting Aβ-HSPG interactions.

Topics: Aged, 80 and over; Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Animals; Disease Models, Animal; Heparitin Sulfate; Hippocampus; Humans; Inflammation; Mice; Neurons; Protein Aggregation, Pathological

Amyloid light chain (AL) amyloidosis is a protein misfolding disease where immunoglobulin light chains sample partially folded states that lead to misfolding and amyloid formation, resulting in organ dysfunction and death. In vivo, amyloid deposits are found in the extracellular space and involve a variety of accessory molecules, such as glycosaminoglycans, one of the main components of the extracellular matrix. Glycosaminoglycans are a group of negatively charged heteropolysaccharides composed of repeating disaccharide units. In this study, we investigated the effect of glycosaminoglycans on the kinetics of amyloid fibril formation of three AL cardiac amyloidosis light chains. These proteins have similar thermodynamic stability but exhibit different kinetics of fibril formation. We also studied single restorative and reciprocal mutants and wild type germ line control protein. We found that the type of glycosaminoglycan has a different effect on the kinetics of fibril formation, and this effect seems to be associated with the natural propensity of each AL protein to form fibrils. Heparan sulfate accelerated AL-12, AL-09, κI Y87H, and AL-103 H92D fibril formation; delayed fibril formation for AL-103; and did not promote any fibril formation for AL-12 R65S, AL-103 delP95aIns, or κI O18/O8. Chondroitin sulfate A, on the other hand, showed a strong fibril formation inhibition for all proteins. We propose that heparan sulfate facilitates the formation of transient amyloidogenic conformations of AL light chains, thereby promoting amyloid formation, whereas chondroitin sulfate A kinetically traps partially unfolded intermediates, and further fibril elongation into fibrils is inhibited, resulting in formation/accumulation of oligomeric/protofibrillar aggregates.

Topics: Amino Acid Substitution; Amyloidogenic Proteins; Amyloidosis; Chondroitin Sulfates; Heparitin Sulfate; Humans; Immunoglobulin kappa-Chains; Mutation, Missense; Protein Aggregation, Pathological