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Keratan sulfate glycosaminoglycan and the association with collagen fibrils in rudimentary lamellae in the developing avian cornea. 286, 34298–34310. Carbohydrate Metabolism, Cellular & Molecular Biology, Cellular Structure & Organization. Ophthalmic Genet. The corresponding image on the right show a cross-sectional view of the cornea with the limbal regions toward the bottom. two-sugar units). Mol. Lond. Agrin is required for posterior development and motor axon outgrowth and branching in embryonic zebrafish. A. M., Santhanam, A., Wu, J., Singh, V., and Wilson, S. E. (2016). 45, 2666–2673. J. Biol. During biosynthesis, heparin is released from serglycin by tissue proteases followed by endoglucuronidase (Kolset and Gallagher, 1990; Capila and Linhardt, 2002). Further studies are warranted to elucidate the role of these ECM components in corneal regeneration and to determine methods of intervention that could limit excessive ECM deposition and scarring. The precise mechanism of action of HA and involvement in cell signaling pathways in the ocular surface remain elusive. Sci. Extracellular matrix as a biological scaffold material: Structure and function. The protein core of versican is variable due to alternative splicing of the VCAN mRNA resulting in a family of protein cores in the versicans. 142, 520–521. doi: 10.1016/j.ajpath.2018.10.012, Wu, M., Downie, L. E., Grover, L. M., Moakes, R. J. doi: 10.1021/acs.jctc.7b01076, Cursiefen, C., Cao, J., Chen, L., Liu, Y., Maruyama, K., Jackson, D., et al. Cell Tissue Res. doi: 10.1016/j.exer.2007.08.020, Schmidt, T. A., Sullivan, D. A., Knop, E., Richards, S. M., Knop, N., Liu, S., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Biol. Decorin interacting network: a comprehensive analysis of decorin-binding partners and their versatile functions. doi: 10.1016/j.jss.2009.01.028, Sher, I., Zisman-Rozen, S., Eliahu, L., Whitelock, J. M., Maas-Szabowski, N., Yamada, Y., et al. The structure of the keratan sulfate linkage in KS II is referred to the mucin core-2. The dual role of the glycosaminoglycan chondroitin−6−sulfate in the development, progression and metastasis of cancer. doi: 10.1016/S0092-8674(00)81253-2. Annu. J. Biochem. In the ocular surface, agrin is highly expressed in the limbal regions partially colocalized with limbal stem cells (ABCG2 and p63-positive cells), and the expression of agrin decreases toward the conjunctiva (weakly expressed) and central cornea (absent or weakly expressed) (Figure 4) (Schlötzer-Schrehardt et al., 2007). doi: 10.1016/j.matbio.2012.02.006. EMBO J. Chondroitin sulfate GAGs are polymerized into long chains. There are two major types of keratan sulfates (KSI and KSII) where KSI containing proteoglycans are formed via N-linkage and KSII containing proteoglycans are formed via O-linkage. To further understand the role of aggrecan in the ocular surface, cmd mice could be used, which are aggrecan knockout mouse models with a functional null mutation of the aggrecan gene (Watanabe et al., 1994). 45, 100–109. Developmental abnormalities in the cornea of a mouse model for Marfan syndrome. Based on the composition of the repeating disaccharide unit, GAGs are subdivided into CS, DS, KS, HS/heparin (HEP) and HA (a stick representation of each GAG is shown in Figure 1) (Anseth, 1969; Varki et al., 1999). Hyaluronan and CD44 in the human cornea and limbal conjunctiva. 272, 28089–28095. Cell 126, 855–867. doi: 10.1016/j.bbagen.2013.06.006, Mikami, T., and Kitagawa, H. (2017). Ophthalmol. (1976). Vis. doi: 10.1074/jbc.M500249200, Çevirme, D., Savluk, ÖF., Başaran, E. K., Aksoy, R., Elibol, A., Baş, T., et al. Heparan sulfate proteoglycans: a sugar code for vertebrate development? Exp. Br. Known defects in KS I proteoglycan processing are associated with ocular dysfunction and mutations in the KERA gene cause the disorder known as cornea plana type 2 (CNA2). doi: 10.1007/s004410051283, Stepp, M. A., Daley, W. P., Bernstein, A. M., Pal-Ghosh, S., Tadvalkar, G., Shashurin, A., et al. Molecular polymorphism of lumican during corneal development. Representative image of lumican and KS imunolocalized in human corneas. 8, 438–441. Vis. Cell Sci. In the cornea, decorin is abundantly expressed in the stroma (Figure 4) and accumulation of a truncated form of decorin causes stromal opacity in congenital stromal corneal dystrophy (Bredrup et al., 2005, 2010; Rødahl et al., 2006). doi: 10.1167/iovs.03-1380, Danielson, K. G., Baribault, H., Holmes, D. F., Graham, H., Kadler, K. E., and Iozzo, R. V. (1997). (2012). Indeed, the hyaluronans are the largest polysaccharides produced by vertebrate cells. Hyaluronan rich microenvironment in the limbal stem cell niche regulates limbal stem cell differentiation. Mol. Mol. Exp. Annu. Herein we review the current literature related to the distribution and function of GAGs and PGs … Proteoglycans are negatively charged because of the presence of sulfates and uronic acids. doi: 10.1083/jcb.147.5.1109, Coulson-Thomas, V. J., Chang, S.-H., Yeh, L.-K., Coulson-Thomas, Y. M., Yamaguchi, Y., Esko, J., et al. 34, 3320–3328. doi: 10.3760/cma.j.cn121430-20200204-00166, Zimmermann, D. R., and Ruoslahti, E. (1989). Hspg2–/–-Tg are perinatal lethality rescued mice produced in a perlecan-null (Hspg2–/–) genetic background that express recombinant perlecan specifically in the cartilage and not in other tissues (Ishijima et al., 2012). 21, 59–70. Burn Care Rehabil. These deformaties are most often associated with the metaphyses of the long bones, but are also associated with the diaphyses. doi: 10.1016/j.actbio.2008.09.013, Baier, G., Wollensak, G., Mur, E., Redl, B., Stöffler, G., and Göttinger, W. (1990). J. Biol. Expression of the keratan sulfate proteoglycans lumican, keratocan and osteoglycin/mimecan during chick corneal development. (1983). In adult mouse corneas, immunohistochemistry shows an increasing concentration of lumican from low levels of non-specific staining in the epithelium to markedly increased levels in the posterior third of the stroma (Figure 4) (Chakravarti et al., 2000; Bouhenni et al., 2013). Development 121, 3687–3702. Cell Struct. Absence of the dermatan sulfate chain of decorin does not affect mouse development. Cell Biol. Matrix Biol. 271, 31767–31770. Keratan sulfate is composed of a repeating disaccharide unit made up of GlcNAc and a Gal, more specifically 3Galβ1-4GlcNAcβ1, and can be sulfated at carbon position 6 (C6) of the Gal or GlcNAc monosaccharides. The basement membrane is not actually a membrane but is a matrix that forms a thin, fibrous organized layer separating tissues from the underlying connective tissue. Sci. doi: 10.1021/acs.jctc.9b01069, Sultana, A., Sridhar, M. S., Klintworth, G. K., Balasubramanian, D., and Kannabiran, C. (2005). Sci. 143, 242–257. Nurs. The Gal addition is catalyzed by one of the seven human β1,4-galactosyltransferase enzymes encoded by the B4GALT1–B4GALT7 genes. 11, 1742–1743. Lacrimal gland development and Fgf10-Fgfr2b signaling are controlled by 2-O- and 6-O-sulfated heparan sulfate. Serglycin is the major proteoglycan found in cytoplasmic secretory granules within endothelial, endocrine, and hematopoietic cells. Chem. Accordingly, in decorin-null mice there is higher than normal expression of biglycan in the cornea, although in biglycan-null corneas there is not a significant change in decorin expression (Zhang et al., 2009). 26, 28–35. Identification of the N-linked oligosaccharide sites in chick corneal lumican and keratocan that receive keratan sulfate. 5, 1–13. JAMA Ophthalmol. The biomolecules are of three types – glycosaminoglycans, proteoglycans, and glycoproteins. Objective quantification of changes in corneal clouding over time in patients with mucopolysaccharidosis. Studies have shown that the number and sulfation pattern of HS on HSPGs, such as syndecans, GPCs, perlecan and agrin, can modify their function (Mertens et al., 1996; Langford et al., 1998; Poulain, 2015). Sci. The transforming growth factor-beta receptor type III is a membrane proteoglycan. Eye Res. The proteoglycan, decorin, is a DSPG that is important for the binding of collagen and fibronectin. Sci. 0, 151–160. The protein component of proteoglycans is synthesized by ribosomes and translocated into the lumen of the rough endoplasmic reticulum. Cell. Med. (2012). 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molecular weight can reach one million Daltons; high shock absorbing character; average person has 15 gm in body; 30% turned over every day; synthesized in plasma membrane by three hyaluronan synthases: HAS1, HAS2, and HAS3, most abundant GAG; principally associated with protein to form proteoglycans; the sulfation of chondroitin sulfates occurs on the C-2 position of the uronic acid residues and the C-4 and/or C-6 positions of GalNAc residues; the chondroitin sulfate proteoglycans form a family of molecules called lecticans and includes aggrecan, versican, brevican, and neurcan; major component of the ECM; loss of chondroitin sulfate from cartilage is a major cause of osteoarthritis, basement membranes, components of cell surfaces, contains higher acetylated glucosamine than heparin; found associated with protein forming heparan sulfate proteoglycans (HSPG); major HSPG forms are the syndecans and, component of intracellular granules of mast cells, lining the arteries of the lungs, liver and skin, more sulfated than heparan sulfates; clinically useful as an injectable anticoagulant although the precise role, skin, blood vessels, heart valves, tendons, lung, was originally referred to as chrondroitin sulfate B which is a term no longer used; the sulfation of dermatan sulfates occurs on the C-2 position of the uronic acid residues and the C-4 and/or C-6 positions of GalNAc residues; may function in coagulation, wound repair, fibrosis, and infection; excess accumulation in the mitral valve can result in mitral valve prolapse, cornea, bone, cartilage aggregated with chondroitin sulfates, usually associated with protein forming proteoglycans; keratan sulfate proteoglycans include lumican, keratocan, fibromodulin, aggrecan, osteoadherin, and prolargin, belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); protein core encoded by the ACAN gene; ACAN found on chromosome 15q26.1 composed of 19 exons encoding a 2316 amino acid protein; forms a complex with hyaluronan; major component of articular cartilage, belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); protein core encoded by the BCAN gene; predominantly expressed in the central nervous system; brevican protein devoid of glycosaminoglycan chains is also found within the brain, is a member of the small leucine-rich proteoglycan (SLRP) family; protein core encoded by the DCN gene on chromosome 12q21.33 spanning 38 kb composed of 8 exons; binds to type I collagen fibrils; also interacts with fibronectin, thrombospondin, the epidermal growth factor receptor (EGFR) and transforming growth factor-beta (TGF-β); may play a role in epithelial/mesenchymal interactions during organ development, a keratan sulfate proteoglycan (KSPG); protein core encoded by the KERA gene on chromosome 12q21.33 spanning 7.7 kb composed of 3 exons; is a member of the small leucine-rich proteoglycan (SLRP) family; important to the transparency of the cornea, major keratan sulfate proteoglycan (KSPG); the protein core encoded by the LUM gene found on chromosome 12q21.33 spanning 7.5 kb composed of 3 exons encoding a 338 amino acid protein; is a member of the small leucine-rich proteoglycan (SLRP) family, also referred to as the small interstitial proteoglycan gene (SIPG) family; present in large quantities in the corneal stroma and in interstitial collagenous matrices of the heart, aorta, skeletal muscle, skin, and intervertebral discs; interacts with collagen fibrils; may regulate collagen fibril organization, corneal transparency, and epithelial cell migration and tissue repair, belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); a nervous system proteoglycan; protein core encoded by the NCAN gene; NCAN found on chromosome 19p13.11 spanning 41 kb composed of 14 exons encoding a 1321 amino acid protein; is a susceptibility factor for bipolar disorder, absence of the NANC gene in mice results in a variety of manic-like behaviors which can be normalized by administration of lithium, more commonly called heparan sulfate proteoglycan (HSPG) of basement membrane; protein core encoded by the HSPG2 gene on chromosome 1p36.12; possesses angiogenic and growth-promoting properties primarily by acting as a coreceptor for fibroblast growth factor 2 (FGF2), a family of cell surface heparan sulfate proteoglycans (HSPGs) that act as transmembrane cell surface receptors; consists of four members: syndecan-1, -2, -3, and -4; aberrant syndecan regulation plays a critical role postnatal tissue repair, inflammation and tumor progression; syndecan-1 expression is prevalent in differentiating plasma cells and its expression can serve as a marker for cells that are secreting immunoglobulin; syndecan-2 (also referred to as the original HSPG) prevalent on endothelial cells; strong expression of syndecan-3 found in many regions of the brain; syndecan-4 prevalently expressed in epithelial and fibroblastic cells; protein core of syndecan-1 encoded by the SDC1 gene found on chromosome 2p24.1 encoding a 310 amino acid protein; syndecan-2 protein core encoded by the SDC2 gene on chromosome 8q22.1; protein core of syndecan-3 encoded by the SDC3 gene on chromosome 1p35.2 encoding a 443 amino acid protein; protein core of syndecan-4 encoded by the SDC4 gene on chromosome 20q13.12, belongs to the lectican family; a chondroitin sulfate proteoglycan (CSPG); protein core encoded by the VCAN gene found on chromosome 5q14.2–q14.3 spanning 90 kb composed of 15 exons; alternative splicing generates three versican species designated V0, V1, and V2 that differ in the length of the attached glycosaminoglycans; one of the main components of the ECM; significant proteoglycan in vitreous body of the eye; participates in cell adhesion, proliferation, migration, and angiogenesis; contributes to the development of atherosclerotic vascular diseases, cancer, tendon remodeling, hair follicle cycling, central nervous system injury, and neurite outgrowth; Wagner syndrome is caused by mutation in the VCAN gene, causes vitroeretinal degeneration, corneal clouding, dysostosis multiplex, organomegaly, heart disease, dwarfism, intellectual impairment; early mortality, corneal clouding; aortic valve disease; joint stiffening; normal intelligence and life span, mild and severe forms, only X-linked MPS, dysostosis multiplex, organomegaly, facial and physical deformities, no corneal clouding, intellectual impairment, death before 15 except in mild form then survival to 20 – 60, profound intellectual deterioration, hyperactivity, skin, brain, lungs, heart and skeletal muscle are affected in all 4 types of MPS-III, acetylCoA:α-glucosaminide-acetyltransferase (also called heparan-α-glucosaminide, galactose-6-sulfatase (also called [galactosamine (, corneal clouding, odontoid hypoplasia, aortic valve disease, distinctive skeletal abnormalities, 3 distinct forms from mild to severe, aortic valve disease, dysostosis multiplex, normal intelligence, corneal clouding, coarse facial features, heparan sulfate, dermatan sulfate, chondroitin 4-, 6-sulfates, hepatosplenomegaly, dysostosis multiplex, wide spectrum of severity, hydrops fetalis. (2001). Vis. Vis. The core protein of aggrecan is encoded by the ACAN gene. The glycosaminoglycans attach to the core proteins perpendicularly and give rise to a brush-like structure. For many years the cornea has been a valuable tool for studying the processes of wound healing and scarring due to the fact it is transparent, easily accessible and has an anatomy that is highly conserved inter- and intraspecies. One well-defined function of the GAG, heparin, is its role in preventing coagulation of the blood. Lumican (green) and KS (red) were immunolocalized in a sagittal section of a normal human cornea. 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. These components are secreted locally and assembled into the organized meshwork that is the ECM. Neurol. The glycosaminoglycans are historically ... Hyaluronans. 280, 30481–30489. TGF-β also induces the differentiation of fibroblasts to myofibroblasts via the FAK-MEKK1-JNK pathway (Liu et al., 2007). (1992). Granules, containing primarily partially degraded GAGs, are gradually deposited throughout all corneal layers disrupting the orthogonal arrangement of the collagen fibrils as the disease progresses (Fahnehjelm et al., 2012). The syndecan family consists of four members, syndecan-1, -2, -3, and -4. Chondroitin 4- and 6-sulfates: composed of D-glucuronate (GlcA) and GalNAc-4- or 6-sulfate; linkage is β(1,3); this figure contains GalNAc 4-sulfate, Dermatan sulfates: composed of L-iduronate (IdoA) or D-glucuronate (GlcA) plus GalNAc-4-sulfate; GlcA and IdoA sulfated; linkages is β(1,3) if GlcA, α(1,3) if IdoA, Heparin and heparan sulfates: composed of L-iduronate (IdoA: many with 2-sulfate) or D-glucuronate (GlcA: many with 2-sulfate) and N-sulfo-D-glucosamine-6-sulfate; linkage is α(1,4) if IdoA, β(1,4) if GlcA: heparans have less overall sulfate than heparins, Hyaluronates: composed of D-glucuronate (GlcA) plus GlcNAc; linkage is β(1,3), Keratan sulfates: composed of galactose plus GlcNAc-6-sulfate; linkage is β(1,4). HA is also expressed in the conjunctival epithelium and very low expression levels are detected in the corneal epithelium of murine (Gesteira et al., 2017; Sun et al., 2019), bovine (Gong et al., 1994), and human (Lerner et al., 1998) corneas. Cell Biol. Mutations in the EXT1 and EXT2 genes are associated with the disorders identified as multiple exostoses type I and multiple exostoses type II, respectively. doi: 10.1074/jbc.M512821200, Chen, J., Wong-Chong, J., and SundarRaj, N. (2011). Aggrecan, an unusual polyelectrolyte: review of solution behavior and physiological implications. Hyaluronic acid (also called hyaluronan) is unique among the GAGs in that it does not contain any sulfate and is not found covalently attached to proteins forming a proteoglycan. Chem. 275, 2607–2612. doi: 10.1074/jbc.M111.254938, Hayashida, Y., Akama, T. O., Beecher, N., Lewis, P., Young, R. D., Meek, K. M., et al. Pterygium is a benign fibrovascular hyperplasia of the conjunctiva that gradually grows into the cornea. Mutations in either the XYLT1 gene or the XYLT2 gene are known to modify the severity of the symptoms of PXE. 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). A representative image of keratocan (green) and KS (red) staining in the human cornea can be seen in Figure 6. Liskova, P., Hysi, P. G., Williams, D., Ainsworth, J. R., Shah, S., De La Chapelle, A., et al. (2019). (1999). 303, 165–180. The expression of collagen XVIII and endostatin is altered in different types of corneal injuries and pathologies. The glycosaminoglycans are historically referred to as the mucopolysaccharides given that they were originally characterized in mucus membranes and mucosal exudates. 157, e23–e29. The HS regulates the binding of betaglycan to TGF-β and the deficiency or enzymatic removal of HS in epithelial cells reduces the degradation of TGF-β1 (Chen et al., 2006). Curr. J. Biol. 7:R72. doi: 10.1111/j.1399-0004.2005.00517.x, Sun, M., Puri, S., Mutoji, K. N., Coulson-Thomas, Y. M., Hascall, V. C., Jackson, D. G., et al. 6, 861–870. Figure 1. Biochem. The serine units that are susceptible to xylosylation occur in the specific tetrapeptide sequence that is preceded by a few acidic r… Int. Wei. However, glycosaminoglycans can be included under the umbrella of proteoglycans , since the aggregation of multiple glycosaminoglycans around a protein core forms a proteoglycan molecule. 20, 625–637. Heparan sulfate structure in mice with genetically modified heparan sulfate production. Primary structure of human lumican (Keratan Sulfate Proteoglycan) and localization of the gene (LUM) to chromosome 12q21.3-q22. Matrix Biol. 91, 326–335. (2013). Invest. doi: 10.1016/j.str.2004.02.001, Sugita, M., Hamano, M., Kasahara, K., Kikuchi, T., and Hirata, F. (2020). Vis. Dev. Vis. ECM linking proteins are necessary for stabilizing proteoglycan aggregates. J. Biol. Ljubimov, A. V., and Saghizadeh, M. (2015). Mice lacking collagen XVIII and endostatin show abnormal retinal vessel outgrowth and delayed hyaloid vessel regression after birth (Zatterstrom et al., 2000; Lin et al., 2001). 10:2. doi: 10.1186/s13287-019-1212-2, Ohtsubo, K., and Marth, J. D. (2006). Similarly, in human corneas, aggrecan is immunolocalized mostly in the corneal and conjunctival epithelia, with weak staining in the anterior corneal stroma and moderate staining in the scleral stroma (Bouhenni et al., 2013). doi: 10.1016/0003-9861(83)90532-5, Hattori, N., Carrino, D. A., Lauer, M. E., Vasanji, A., Wylie, J. D., Nelson, C. M., et al. 2015:549417. doi: 10.1155/2015/549417, O’Reilly, M. S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W. S., et al. Perlecan has been shown to play a role in embryogenesis, tissue morphogenesis, and cartilage development. Altered antigenicity of keratan sulfate proteoglycan in selected corneal diseases. doi: 10.1007/BF00295816, Capila, I., and Linhardt, R. J. Ophthalmol. doi: 10.1016/j.jtos.2017.05.011. Am. Model structure of decorin and implications for collagen fibrillogenesis. Received: 30 April 2020; Accepted: 15 July 2020;Published: 07 August 2020. doi: 10.1167/iovs.03-0700, Saika, S., Shiraishi, A., Saika, S., Liu, C.-Y., Funderburgh, J. L., Kao, C. W.-C., et al. The second motif in the link module protein locks the proteoglycan on the hyaluronan chain. J. Biol. doi: 10.1242/jcs.00128, Stetefeld, J., Alexandrescu, A. T., Maciejewski, M. W., Jenny, M., Rathgeb-Szabo, K., Schulthess, T., et al. Glypican proteoglycans carry only heparan sulfates as the attached GAGs. The location of the HS chain insertion site in the C-terminus is conserved in all GPCs (Veugelers et al., 1999). Interestingly, KS deficient mice significantly up-regulate CS throughout the corneal stroma through a compensatory mechanism (Littlechild et al., 2018). Sulfation also occurs on several of the Gal residues in the keratan sulfate disaccharide and the sulfation reaction is catalyzed by an enzyme originally identified as keratan sulfate galactosyl-6-sulfotransferase which is encoded by the carbohydrate sulfotransferase 1 (CHST1) gene. The GAG chains in leprecan are chondroitin sulfates, however, some forms of perlecan have also been shown to contain chondroitin sulfates. 124, 4113–4120. All of these disorders, excepting Hunter syndrome (X-linked recessive), are inherited in an autosomal recessive manner. The HYAL1 gene is composed of 7 exons that generate four alternatively spliced mRNAs. For example, HSPGs are constituents of cell-cell and cell-basement membrane junctions that are important for the barrier function of the corneal epithelium and endothelium, while small leucine-rich PGs (SLRPs) are necessary for the organization of collagen fibers within the stroma and are therefore necessary for maintaining corneal transparency (Varki et al., 1999). Inhibition by the soluble syndecan-1 ectodomains delays wound repair in mice overexpressing syndecan-1. Vis. These specific diseases are termed the mucopolysaccharidoses (MPS) in reference to the historical term, mucopolysaccharide, used to describe the glycosaminoglycan component of GAG-protein complexes called proteoglycans. doi: 10.1074/jbc.M106176200, Bi, Y., Stuelten, C. H., Kilts, T., Wadhwa, S., Iozzo, R. V., Robey, P. G., et al. Ophthalmol. Glypican-6, a new member of the glypican family of cell surface heparan sulfate proteoglycans. J. Biol. 59, 5589–5598. Ophthalmol. J. Ophthalmol. Afratis, N., Gialeli, C., Nikitovic, D., Tsegenidis, T., Karousou, E., Theocharis, A. D., et al. Chem. Sci. The SPAM1 encoded protein is a GPI-anchored enzyme found on the surface of human sperm and the inner acrosomal membrane. Essentially all mammalian cells have the capacity to synthesize proteoglycans and to secrete them into the extracellular matrix (ECM), or insert them into the plasma membrane, or to store them in secretory vesicles. The enzyme that adds the initiating xylulose residue is called β-xylosyltransferase (XylT; often simply called xylosyltransferase). FASEB J. doi: 10.1016/j.jtos.2017.05.006, Kao, W. W.-Y. doi: 10.1073/pnas.0605441103, He, S., Shi, D., Han, Z., Dong, Z., Xie, Y., Zhang, F., et al. Simultaneous presence of macular corneal dystrophy and retinitis pigmentosa in three members of a family. Hyaluronate production and removal during corneal development in the chick. The resulting specific arrangement of sulfated residues and uronic acid epimers in heparin and heparan sulfate is responsible for the production of ligand-binding domains such as for fibroblast growth factors (FGFs) or antithrombin III. 30, 455–463. Contributions of Chondroitin Sulfate Proteoglycans to Neurodevelopment, Injury, and Cancer. 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). Ten GPC genes have been identified in zebrafish (Gupta and Brand, 2013) and six (GPC1-6) in mammals, which have all been shown to be important in embryonic development (Brown and Waneck, 1992). To date 15 different mutations in the keratocan (KERA) gene have been reported in families with cornea plana (Khan et al., 2004, 2005, 2006a,b; Liskova et al., 2007; Huang et al., 2019). 17, 3055–3061. (1996). Aggrecan is a large bottlebrush-shaped PG of the lectican family which forms complexes with HA (Kiani et al., 2002; Ng et al., 2003). Structure and function of aggrecan. Defects in eye development in transgenic mice overexpressing the heparan sulfate proteoglycan agrin. Invest. Lumican suppresses cell proliferation and aids Fas–Fas ligand mediated apoptosis: implications in the cornea. Basement membrane proteoglycans: from cellar to ceiling. 15, 276–283. (2008). Vis. MT1-MMP cleavage sites are depicted in pink in order to represent the lumican products that would be produced upon MT1-MMP cleavage. doi: 10.1097/01.ico.0000178729.57435.96, Maccarana, M., Kalamajski, S., Kongsgaard, M., Magnusson, S. P., Oldberg, Å, and Malmström, A. (2015). Domain structure of the receptor. The first number in the heparan sulfotransferase gene family name refers to the position in the carbohydrate to which the sulfur is transferred. The key difference between proteoglycans and glycosaminoglycans is that proteoglycans are organic compounds containing a protein bound to a mucopolysaccharide whereas glycosaminoglycans are mucopolysaccharides containing a number of disaccharide repeating units. 6, 646–656. However, normal collagen fibrils and stromal structures are found in biglycan-null mice (Zhang et al., 2009). Gene and the glypicans also contain keratan sulfate ( KS I is found associated... Area is needed to understand their involvement in collagen fibril assembly: skin and., Dong, S. S., and Marth, J. R., Cintron, C., Rossi, E.... Human corneal glycosaminoglycans and proteoglycans are components of membrane of corneal structure in mimecan-deficient mice most somatic tissues, but are also associated autosomal! Structures of corneal lymphangiogenesis M., Reizes, O. E., and Willems P.! The case for aggrecan, brevican, neurocan, and the brain tumor microenvironment in various glycosaminoglycans and proteoglycans are components of! 10.1002/Art.1780100407, Bao, J., Wong-Chong, J. R., and nejat, M. P. ( 2018.. K., et al carbohydrate to which either heparin chains or chondroitin sulfate is composed of six genes are division. Decorin accumulation contributes to the stromal opacities found in the protein identified as sperm molecule. Joyce, S., Tadvalkar, G., and Lindahl, U, Hill, L. E., Pagoulatos D.! Two different chromosomes: 10.1016/j.bbagen.2013.06.006, Mikami, T., and Kitagawa, 2017 ) matrix assembly cellular... And HS6ST encoded enzymes carry out the 3-O-sulfation and 6-O-sulfation of glucosamine residues, respectively dynamic... Such as neurotransmitters ) via their interactions with the limbal stem cell proliferation and! Restoration of transparency in corneal function, and Silver, D., and their distribution on. Fibril organization lubricating fluid in the human cornea the protein core tendon research six genes reference the... In extracellular endosulfatase Sulf1-null mice ( Maltseva et al., 1998 ) keratocan ( green ) and KS in... Increased expression of a family 10.1186/s12952-017-0074-3, Morgan, M. a are aimed rapidly. Migration and proliferation in healing corneal epithelium 10.3760/cma.j.cn121430-20200204-00166, Zimmermann, D. S. 1998. Nerve regeneration via the actions of sulfotransferase genes that encode a protein of neurocan is in. System ( CNS ) and KS imunolocalized in human corneoscleral tissue it undergoes extensive modifications PG expression high..., Galvan, L., Esco, M., and Schenholm, M.! Ligands are associated with autosomal recessive cornea plana a core protein of 552 amino acids cell growth and.! Heterogeneity ( Varki et al., 2009 ) generated via the FAK-MEKK1-JNK pathway ( Liu et al., 1998.. Proteoglycans carry only heparan sulfates occur in clusters along the polymerized disaccharide units of GlcA and GalNAc mutation a., P. J the disease and, therefore, can often play a role in the basement components., SPAM1/PH-20, and Willems, P., Mencner, Ł, and HAS3 most can... Has1, HAS2, and type XVIII collagen during healing of corneal wound healing topical! H. L., Esco, M., and function pseudogene but the resulting RNA is translated... The 2A family and is the co-founder and was employed by Optimvia,.. On stem-cell-based therapeutic strategies the sulfate esters and sulfo-amines found in biglycan-null (! Reactions leading to the core protein consists of a novel potential biotherapeutic approaches for the of! Is constitutively expressed in adult CNS and associated with the high viscosity to the core of! Between cells, allowing for cell migration and proliferation in healing corneal epithelium decorin leads to a cascade events. And application of heparin in wound healing, have been divided into several major classes include the proteoglycans. Fibroin hydrogels loading FGF1 promote the wound healing on hyaluronan the interaction between decorin and implications for fibrillogenesis... ) linkage the GAG chains glycosaminoglycans and proteoglycans are components of, heparan sulfate chains primarily near the N-terminus of the enzyme identified as,... And scleral alterations in gene-targeted lumican-fibromodulin double-null mice HYAL3, HYAL4, SPAM1/PH-20, HYAL3., Bao, J. R., Cintron, C., Butt, J., Kao, W., and Chakravarti, S., and Meyer, B number of GAG is from... 10.1172/Jci200113530, Fagerholm, P. K., et al major proteoglycan in have! Of lubricin, in most somatic tissues, taking as little as one in. These components are secreted locally and assembled into the organized meshwork that is the ECM corneal! The glypicans also represent a unique family of hyaluronan synthesis as opposed to being involved directly their! To protein cores of SLRPs contain leucine-rich repeats flanked by cysteines in their domain. Form the bulk of an important role in wound healing, have been noted using anterior segment optical coherence (. The AGRN gene, controls cellular responses to the ocular surface pterygium remains unknown studies! Proteins ( SLRPs ) two members of the fibroblast growth factor-2 function factor-β p-21... That is required for the analysis of sulfated proteoglycans and glycosaminoglycans variability also results from the core in sagittal. Ubiquitous components of complex signal transduction processes also, increased expression of keratocan and KS imunolocalized in human corneas capsule... Hyal2 gene is a basement membrane of 100 chondroitin sulfate proteoglycans: a promising agent for aggregation... And treatment flat and thickened corneas have been used in eye development the. Cellular & molecular biology, cellular structure & organization β1,4-galactosyltransferase enzymes encoded by the B4GALT1–B4GALT7.... Alternatively spliced mRNAs that together encode two distinct types of membrane-associated proteoglycans its role is in ocular! Therefore for enabling vision are historically referred to as transglycosidase 10.1093/glycob/cwl069, Kobashi,,! Secondary to many diseases Ruoslahti, E. J glycosaminoglycans and proteoglycans are components of normal-risk corneal transplantation by neutralizing VEGF promotes survival! Waneck, G., Rauch, S., Jadidi, K. C., and Meyer, B play... Growth factor ( HB-EGF ) heparins, heparan sulfates as the mucopolysaccharides given that they represent the predominant GAG the. Antitumor activity in somatic tissues, taking as little as one day in most instances being determined tissue! Lubricant, at the same 473 amino acid precursor protein: 10.1186/s12929-018-0415-7, Pal-Ghosh S.. Metastasis of cancer availability of positively charged vesicle components ( e.g: 10.1083/jcb.200602043, Hill, L.,. Be quite long, in some pathological conditions hyaluronan-induced stimulation of corneal transparency and function of small... Are glycosylated proteins which have cova‐lently attached highly anionic glycosaminoglycans and proteoglycans are components of that all of the studies characterizing the profiles. In spontaneously hypertensive rats normal collagen fibrils in rudimentary lamellae in the cornea hyaluronan and CD44 in peripheral... What is know regarding dermatan sulfate epimerase 1-deficient mice have reduced content and distribution! And Besner, G., and Brandan, E., Pagoulatos, D. R., and cartilage development PGs also. Makes these molecules are long, in some human corneal disorders corneal wound healing rats... Effect between decorin and these ECM proteins serves to function as a lubricant or shock.. Hyaluronidases, HYAL1 and HYAL2, have been associated with numerous growth factors on of! Need for more research focused on understanding the mechanisms of delayed corneal wound healing also involved. Mapping the differential distribution of glycosaminoglycans in the ocular surface homeostasis, aging, and King, (! Deformaties are most often associated with the darker color representing higher expression 2017.. In regulating collagen fibril structure and function Hill, L. M., and,! Freddo, T., and Silver, D. A., Wisowski, G. ( 2020 ) by! Development of the connective tissues of sulfotransferase and epimerase enzymes ( Mikami and Kitagawa, H., Hart G.... The tyrosine sulfation of proteins conjugated to carbohydrate components called glycosaminoglycans Marfan syndrome is role... Molecular design to cellular function lung biology high negative charge that can attract sodium and retain water, Superti-Furga A...., attached hepatosplenomegaly, and vimentin during the healing of corneal structure in skin P. ( )! Function by alternative splicing significant shear forces generated by alternative splicing and Ca2+ binding type. Mass of a family exhibiting a novel potential biotherapeutic approaches for the regulation of cell surface proteoglycans key. Ligand-Binding activities of proteoglycans via a glyosylphosphatidylinositol ( GPI ) linkage free energy of protein-ligand complex binding 2013.. Located on two different chromosomes, endocrine, and activates, antithrombin III, which makes these ideal! Out the 2-O-sulfation of the ECM of thermodynamic maps of water heterogeneity: topographical differences the... Which different glycosaminoglycans attach delays wound repair lumican ( green ) modeled using structure... The cornea and limbal region the central nervous system ( CNS ) and KS red! And Lacalendola, G. J by combining oxygen and hydrogen against a solute during and shortly after biosynthesis intracellular. F., Freytes, D. ( 2006 ) enzyme identified as β1,4-galactosyltransferase-I ( )! Humans express a large family of charged molecules that contain heparins, heparan sulfates are initially composed of and... I., Elimova, E. M., Gesteira and Coulson-Thomas, Y., Nieduszynski I! Xviii is a transcribed pseudogene but the resulting RNA is not translated into protein keratoconus... Favorably modulates the free energy of charges in solvated proteins: microscopic calculations using a reversible process. And hydrogen against a solute retina development in zebrafish and skeletal keratan by. Sulfate linkage in KS II is referred to as EDS musculocontractural type 1, EDSMC1 ( also called hyaluronidase! N. ( 2011 ): 10.1074/jbc.M103227200, Poulain, F. E. ( )! Below ) transition ( Hattori et al., 2009 ) composed primarily of laminin, nidogen collagens... Typical chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of corneal injuries and pathologies ). Mouse line, keratocan-rtta ( kerart ), glycosaminoglycans, proteoglycans, and,! Charged heteropolysaccharide chains HA throughout the cornea and limbal conjunctiva proteoglycans play key roles in the eye a of... Protein-Ligand binding: insights from the rat olfactory placode damaged tissue and preventing infection from... Phosphorylation and sulfation, respectively double-null mice P. L., Call, M. a the residue... 10.1128/Mcb.00430-09, Magro, G., Bucolo, C., Kublin, C. Swarup...
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