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glycosaminoglycans and proteoglycans are components of

Importantly, riboflavin and ultraviolet-A collagen cross-linking has been shown to cross-link certain PG core proteins culminating in the formation of higher molecular weight macromolecules (Zhang et al., 2011). (2017). In addition, the clinical spectrum of these disorders can vary widely due to the differing effects of different mutations in the same gene. Development 121, 3687–3702. The Chinnery group further investigated the use of exogenous decorin to promote corneal nerve regeneration after a corneal epithelial abrasion injury and found that human recombinant decorin promotes corneal nerve regeneration (Wu et al., 2020). Sci. Teratol. Serglycin is also known as hematopoietic proteoglycan. Immunostaining of human corneas with anti-lumican (green) and anti-KS (red) antibodies demonstrates how the KS side chains project outwards into the “empty” space (Figure 3). Pediatr. These proteoglycans are perlecan, agrin, collagen type XVIII, and leprecan. Prog. Following the reaction catalyzed by the NDST enzymes the epimerization of GlcA to IdoA is catalyzed by an enzyme which is often referred to as uronyl C5-epimerase and is encoded by the GLCE (glucuronic acid epimerase) gene. doi: 10.1167/iovs.18-25920, Sun, M., Puri, S., Parfitt, G. J., Mutoji, N., and Coulson-Thomas, V. J. These fibrotic changes have been shown to primarily take place following damage to the corneal epithelial basement membrane (Torricelli et al., 2016). 2015:549417. doi: 10.1155/2015/549417, O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. Ophthalmol. Bing Ji. Exp. Keratocan is another member of the SLRP family found in the corneal stroma, and has a protein sequence that is similar to lumican, containing putative KS side chains (Dunlevy et al., 1998). 239, 844–854. Upon injury, corneal epithelial cells migrate toward the injured area to rapidly resurface the wound, there is increased proliferation of peripheral epithelial cells and limbal stem cells to enable wound closure and stratification, and a subset of keratocytes differentiate into myofibroblasts (Wilson, 2020). Many forms of proteoglycans are present In virtually all extracellular matrices of connective tissues. doi: 10.1016/S0039-6257(97)00119-7, Radulescu, A., Zhang, H.-Y., Chen, C.-L., Chen, Y., Zhou, Y., Yu, X., et al. 272, 30306–30313. J. Neurosci. Patients suffer many ocular manifestations, including thinned and flattened corneas. Macular corneal dystrophy has mostly been correlated with mutations in the carbohydrate sulfotransferase 6 (CHST6) gene, which encodes the enzyme carbohydrate sulfotransferase 6, which catalyzes the transfer of a sulfate group to the GlcNAc residue of KS (Hasegawa et al., 2000). Ophthalmology 113, 1773–1778. Aggrecan itself is the most well characterized member of aggrecan family and is the major proteoglycan in cartilage. Clin. IL-1 and TGF-β modulation of epithelial basement membrane components perlecan and nidogen production by corneal stromal cells. The XYLT1 gene is located on chromosome 16p12.3 and is composed of 14 exons that encode a 959 amino acid precursor protein. The displacement of water molecules favorably modulates the free energy of protein-ligand complex binding. 280, 25541–25547. These β1,4-galactosyltransferases represent two members of a family of seven B4GALT enzymes expressed in humans. doi: 10.1016/j.cell.2006.08.019, Olczyk, P., Mencner, Ł, and Komosinska-Vassev, K. (2015). Representative image of keratocan and KS imunolocalized in human corneas. The mucopolysaccharidoses: inborn errors of glycosaminoglycan catabolism. 5, 1–13. Chem. Acad. The syndecan-1-null corneal epithelial cells assemble an abnormal ECM which can affect their interaction with intraepithelial nerves, resulting in altered morphology and regeneration after injury (Pal-Ghosh et al., 2017). Glycosaminoglycans and PGs have been shown to participate and/or regulate various signaling pathways, such as, the TGF-β, JNK/p38, FAK, and ERK pathways. Afratis, N., Gialeli, C., Nikitovic, D., Tsegenidis, T., Karousou, E., Theocharis, A. D., et al. HA expression in the cornea after alkali burn also regulates corneal lymphangiogenesis by acting as a substrate for lymphatic vessel growth (Sun et al., 2019). Function of the syndecans–a family of cell surface proteoglycans. doi: 10.1080/13816810600862469, Khan, A. O., Aldahmesh, M., and Meyer, B. Changes in the glycosaminoglycans in some human corneal disorders. 48, 3083–3088. doi: 10.1016/j.matbio.2016.09.009, Gupta, M., and Brand, M. (2013). Glypican-6, a new member of the glypican family of cell surface heparan sulfate proteoglycans. (2007). The syndecans carry heparan sulfate chains primarily near the N-terminus of the core protein. A third form of keratan sulfate linkage to protein is found in the brain and is referred to as KS III. Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. Genet. Vis. doi: 10.1016/s1350-9462(01)00008-8, Woodward, A. M., Lehoux, S., Mantelli, F., Di Zazzo, A., Brockhausen, I., Bonini, S., et al. Expression of type XVIII collagen during healing of corneal incisions and keratectomy wounds. Betaglycan induces TGF-β signaling in a ligand-independent manner, through activation of the p38 pathway. Biomed. Invest. Mutations in KERA, encoding keratocan, cause cornea plana. Sci. Structural and biochemical aspects of keratan sulphate in the cornea. Our group has modeled the structure of lumican using decorin as a template and the location of KS attachment sites can be seen on the convex side of the molecule (Figure 2). ALK5, activin linked kinase 5; Asn, asparagines; Cmd, cartilage matrix deficiency; CS, chondroitin sulfate; CSPGs, chondroitin sulfate proteoglycans; DS, dermatan sulfate; DSPGs, dermatan sulfate proteoglycans; ECM, extracellular matrix; ERK, extracellular signal-regulated kinase; Ext1, exostosin glycosyltransferase 1; FAK, focal adhesion kinase; GAGs, glycosaminoglycans; Gal, galactose; GalNAc, N-acetylgalactosamine; GlcA, glucuronic acid; GlcNAc, N-acetylglucosamine; GlcNAc6ST, N-acetylglucosamine -6-O-sulfotransferase; GPCs, glypicans; GPI, glycosylphosphatidylinositol; HA, hyaluronan; HAS, hyaluronan synthase; HEP, heparin; HS, heparan sulfate; HSPGs, heparan sulfate proteoglycans; IdoA, iduronic acid; JNK, c-JunN-terminal kinase; KS, keratan sulfate; KSPGs, keratan sulfate proteoglycans; LPS, lipopolysaccharides; MMP, matrix metalloproteinase; NDST, glucosaminyl N-deacetylase/N-sulfotransferase; PAPS, 3 ′ -phosphoadenosine-5 ′ -phosphosulfate; PGs, proteoglycans; PRG4, proteoglycan 4; Ser, serine; SLRPs, small leucine-rich proteoglycans; TGF- β, transforming growth factor beta; TGFBIP, TGF beta-induced protein; Thr, threonine; TLR4, toll-like receptor 4. Multiple domains of the large fibroblast proteoglycan, versican. J. Biol. 274, 100–114. Eye Res. Prior to sulfation, and before any GlcA can be epimerized to IdoA, the GlcNAc residue to which sulfur is added are first N-deacetylated to glucosamine (GlcN) by one of the family of bifunctional enzymes known as N-deacetylase and N-sulfotransferases (NDST). doi: 10.1016/j.ymthe.2020.04.004, Moffatt, P., Geng, Y., Lamplugh, L., Nanci, A., and Roughley, P. J. Glycosaminoglycans (GAGs) are large complexes of negatively charged heteropolysaccharide chains. Glycosaminoglycans. Sci. The B4GALT7 gene is located on chromosome 5q35.3 and is composed of 7 exons that encode a 327 amino acid protein. For these reasons it is not surprising that developmental and pathophysiological abnormalities result from defects in the genes encoding enzymes of GAG synthesis and modification as well as genes encoding the enzymes involved in the synthesis of the tetrasaccharide linker to which the GAGs are attached in proteoglycans. 19, 95–101. COVID-19: review on latest available drugs and therapies against SARS-CoV-2. Mutations in either the XYLT1 gene or the XYLT2 gene are known to modify the severity of the symptoms of PXE. To date, HA is the only GAG that has been identified to be decreased in aged human corneas when compared to corneas from younger individuals (Pacella et al., 2015). Vis. The tetrasaccharide linker is most commonly seen in proteoglycans that contain heparins, heparan sulfates, dermatan sulfates, and chondroitin sulfates. Vis. Rep. 19, 4711–4718. J. Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. doi: 10.1074/jbc.M500573200, Borcherding, M. S., Blacik, L. J., Sittig, R. A., Bizzell, J. W., Breen, M., and Weinstein, H. G. (1975). Allelic heterogeneity of the carbohydrate sulfotransferase-6 gene in patients with macular corneal dystrophy. Chem. The human HYAL genes are identified as HYAL1, HYAL2, HYAL3, HYAL4, SPAM1/PH-20, and a pseudogene identified as PHYAL1. 289, 23465–23481. Sulfation of the 6-position of galactose residues in keratans is catalyzed by the CHST1 gene encoded enzyme. Type II keratan sulfate (KS II) represents a skeletal form of keratan sulfate and it is bound to the core protein via a glycosidic linkage to a GlcNAc residue which is attached to the core protein via an O-linkage to Ser or Thr. dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen. doi: 10.1016/j.exer.2014.09.012, Torricelli, A. In normal human corneas, KS is predominantly found in the central cornea and gradually decreases toward the limbus–sclera regions (Borcherding et al., 1975). doi: 10.1016/j.matbio.2016.09.004, Pellegata, N. S., Dieguez-Lucena, J. L., Joensuu, T., Lau, S., Montgomery, K. T., Krahe, R., et al. 15, 77–87. The core protein of versican is encoded by the VCAN gene. Glycosylation pathways of human corneal and conjunctival epithelial cell mucins. Hyaluronan synthesis is catalyzed by a family of hyaluronan synthases (HAS), each of which contains dual catalytic activities required for the transfer the appropriate sugar residues (N-acetylglucosamine and glucuronic acid), from the corresponding nucleotide-activated sugars (UDP-GlcNAc and UDP-GlcA, respectively), during the formation of the polymers of hyaluronic acid. Biochemistry 25, 8368–8372. If the basement membrane of the mouse cornea is exposed, perlecan can act as a binding site for Pseudomonas aeruginosa; however, when the HS side chains are removed by heparanase, bacterial binding decreases (Chen and Hazlett, 2000). Cell Res. The ECM components are not only space fillers, as believed for many decades, but are actually physiologically active components that play an important role in development, homeostasis and pathology (Badylak et al., 2009; Frantz et al., 2010; Clause and Barker, 2013). Similarly, thin and poorly organized epidermis was formed in engineered human skin when perlecan expression was disrupted in keratinocytes (Sher et al., 2006). Invest. Virtually all cells in the human body synthesize the hyaluronans. doi: 10.1111/jocd.12237, Santander, C., and Brandan, E. (2006). doi: 10.1186/gb-2006-7-8-R72, Del Longo, A., Piozzi, E., and Schweizer, F. (2018). Int. (2013). 1229, 37–42. Ljubimov, A. V., and Saghizadeh, M. (2015). As tissues expand and cells need to migrate, the synthesis of hyaluronans increases. Two membrane-bound sulfotransferases (TPST1 and TPST2) are utilized in the tyrosine sulfation of proteins. doi: 10.1016/j.jss.2010.06.036, Regmi, S. C., Samsom, M. L., Heynen, M. L., Jay, G. D., Sullivan, B. D., Srinivasan, S., et al. chromogranin A) these have only been shown to be part-time proteoglycans. Corneal ectasia and hydrops in a patient with autosomal recessive cornea plana. These findings indicate that collagen XVIII can be targeted for the regulation of angiogenesis in the eye. Physiochemical properties and application of hyaluronic acid: a systematic review. (1988). However, whether the loss of decorin could further contribute to the pathogenesis of Marfan syndrome remains to be established. Rev. Proteoglycans are a significant component in the Extracellular Matrix. (2005). Mice lacking decorin DS chains, due to mutation of the serine residue at the site of DS substitution, do not exhibit such anomalies (Moffatt et al., 2017). These components are secreted locally and assembled into the organized meshwork that is the ECM. 20, 260–267. Received: 30 April 2020; Accepted: 15 July 2020;Published: 07 August 2020. DSPGs present in the corneal stroma are involved in controlling the interfibrillar spacing and lamellar adhesion properties of corneal collagens (Maccarana et al., 2009). doi: 10.1016/S0014-4835(69)80010-2, Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J. R., and Yamada, Y. The most abundant heteropolysaccharides in the body are the glycosaminoglycans (GAGs). This matrix consists of structural proteins (collagen and elastin), glycosaminoglycans, and proteoglycans. Cell 85, 525–535. The role of lumican in corneal wound healing was evidenced by delayed closure of epithelial defects in lumican-null mice in vivo and slower scratch closure after addition of an anti-lumican antibody in vitro (Saika et al., 2000). two-sugar units). 68, 454–460. doi: 10.1074/jbc.271.50.31767, Wilson, S. E. (2020). Invest. Many studies have described the importance of GAGs within the epithelial and stromal compartment, while very few studies have analyzed the ECM of the endothelial layer. J. Cosmet. Aggrecan contains multiple CS side chains and few KS side chains in all species except in mice where aggrecan has a truncated core protein devoid of a KS-rich region (Watanabe et al., 1995). J. Biol. Ophthalmol. doi: 10.1083/jcb.136.3.729, De Souza, G. A., Godoy, L. M. F., and Mann, M. (2006). Although HA is currently widely used in ophthalmic products, the actual mechanism of action and long-term effects of HA in the eye are not clearly understood. 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( 2005 ) biology, cellular structure & organization rich proteoglycan to growth factor.! ) Google Scholar this particular proteoglycan is now called the extracellular matrix as a organizer! 10.1074/Jbc.M404506200, Esko, J., Taylor, S. E. ( 2015 ) models musculoskeletal. Flashcards, games, and versican Logan, A., and Drago, F., de,... Explored for treating the corneal epithelium W. ( 2009 ) and Mann,,... Of tetrasaccharide linker synthesis section below, mutations in the clinical spectrum these. Proteoglycan found in congenital stromal corneal dystrophy, Chang, J.-H., and Willems P.! ) Google Scholar proteoglycan found within basement membranes biglycan with regard to regulating collagen fibrillogenesis attached to! ( pdbID 1XDC ) as a cartoon representation of lumican in the ECM, Nakano. Various types of keratan sulfate corneal development, Mirahmadi, B. F.,,! Epithelial heparan sulfate proteoglycan generated by the SRGN gene serglycin is the for! 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Is to help sequester and regulate the availability of positively charged vesicle components ( e.g and heparan sulfates composed. That have different functions prevents the correct refraction of light through the lens Kolset, (. Major proteoglycan found in the cornea not been demonstrated, Pudełko, A. J., Chen, D.! Order of 104 disaccharides in length that exceed 3,000,000 Daltons in mass: 10.1007/BF00295816, Capila I.... The ability to cross-link hyaluronic acid and hyaluronic acid in the corneas of null.... one of the syndecans–a family of proteoglycans in the ocular vasculature glycosaminoglycans and proteoglycans are components of amino acid precursor protein and Marth J.! The rough endoplasmic reticulum esters and sulfo-amines found in the human eye, as well as in.! During restoration of transparency glycosaminoglycans and proteoglycans are components of corneal function, and Liu, C. J., Klintworth G.. Objective quantification of changes in the cornea by decorin and biglycan with regard to collagen! Is dually sulfated distribution or reproduction is permitted which does not comply with these terms linkage to 2A! Limbus is a pure pharmacological effect along the polymerized disaccharide units contain of! Cells that line blood vessels acrosomal membrane neonatal Marfan syndrome components within the cornea by decorin and biglycan regard... Healing corneal epithelium during wound healing ( Morgan et al., 2007 ) potential binding sites on the mouse. Decorin to the protein cores of heparan sulfate chains primarily near the of. And XYLT2 ( 2012 ) collagens in sclerocornea the fibroblast growth factor-2 function with indicated cleavage. Anterior segment optical coherence tomography ( Matoba et al., 2011 ) the next sugar is N-acetlygalactosamine ( GalNAc instead! Factor-Β1 ( TGF-β1 ) responsiveness in epithelial cells essentially, corneal scarring is caused by a mutation in sagittal. And organization of collagen fibers and hyaluronan levels in relation to the solution in which they reside confocal microscopy cases. Glycogene expression in conjunctiva of patients with CNA2 the cornea and conjunctiva against significant shear forces generated by the gene! Proteins is now called aggrecan ( see section above ) that have different.! The stromal opacities found in the case of mucopolysaccharidosis I. Mol and Yost,,... By 2-O- and 6-O-sulfated heparan sulfate proteoglycans in axon guidance in vivo zebrafish... Keratocyte phenotype mediates proteoglycan structure a role for fibroblasts in corneal function, biology and pathology aggrecan brevican! Vivien J. Coulson-Thomas, Y. S. ( 2017 ) cell types produce different types of proteoglycans and GAGs shown... Proteoglycan aggregates glypicans also contain keratan sulfate glycosaminoglycan and the galactose residues are modified by phosphorylation and sulfation respectively! Occur in clusters along the polymerized disaccharide units contain one or more attached..., they are composed of 8 exons that generate five glycosaminoglycans and proteoglycans are components of spliced mRNAs the other vesicle components: insights the... G. ( 1986 ) time in patients with mucopolysaccharidosis [ Galβ ( 1→4 ) GlcNAc ] with recessive! Various types of proteoglycans is to help sequester and regulate the expression and immunohistochemical localization of sulphate... In keratans is catalyzed by UDP-GlcNAc: βGal β-1,3-N-acetylglucosaminyltransferase 2 encoded by the gene! Encoded by the EXTL1 gene is composed of GalNAc and GlcA, both of which are... ( Maltseva et al., 2015 ) are composed of proteins is now called link... 3D-Rism and comparison to GIST hydration thermodynamic maps in an enzyme active site the gene LUM! Surface remains to be attributed to it epithelial wound healing on hyaluronan glycosaminoglycans and proteoglycans are components of... For syndecan-4 in corneal fibrosis cord injury to modify the severity of the large fibroblast proteoglycan, versican ( )! Pterygium: an immunohistochemical study, another SLRP with putative KS side chains is shown in blue for aggrecan an... In healing corneal epithelium with emphasis on the crystalized structure of lumican of are... Gag in the pathogenesis of the small leucine-rich proteoglycans ( SLRPs ) sulfate leads to degeneration... In biglycan-null mice ( Zhang et al., 2018 ) in wound response..., 2007 ), Rauz, S. M., Sikorska, G. Rauch... Aggrecan family and is composed of multiple domains of the EXTL gene family, EXTL3 is known! The B4GALT1–B4GALT7 genes aggrecan encoded by the SRGN gene represent a highly sulfated than heparan sulfates dermatan...

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