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The most abundant heteropolysaccharides in the body are the glycosaminoglycans (GAGs). These molecules are long unbranched polysaccharides containing a repeating disaccharide unit. The disaccharide units contain either of two modified sugars, N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc), and a uronic acid such as glucuronate (GlcA) or iduronate. GAGs are highly negatively charged molecules, with extended conformation that imparts high viscosity to the solution in which they reside. GAGs are located primarily on the surface of cells or in the extracellular matrix (ECM) but are also found in secretory vesicles in some types of cells.

Along with the high viscosity of GAGs comes low compressibility, which makes these molecules ideal for a lubricating fluid in the joints. At the same time, their rigidity provides structural integrity to cells and provides passageways between cells, allowing for cell migration. The specific GAGs of physiological significance are hyaluronic acid, dermatan sulfate, chondroitin sulfate, heparin, heparan sulfate, and keratan sulfate. Although each of these GAGs has a predominant disaccharide component (see Table below), heterogeneity does exist in the sugars present in the make-up of any given class of GAG.











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. It is, however, a component of non-covalently formed complexes with proteoglycans in the ECM. Hyaluronic acid polymers are very large (with molecular weights of 100,000–10,000,000) and can displace a large volume of water. Indeed, the hyaluronans are the largest polysaccharides produced by vertebrate cells. The immense size of these molecules makes them excellent lubricators and shock absorbers in the joints.

Structure of the disaccharide component of hyaluronates


composed of D-glucuronate (GlcA) plus GlcNAc; linkage is β(1,3)
Structure of the disaccharide component of dermatan sulfates

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
Structure of the disaccharide component of chondroitin sulfates

Chondroitin 4- and 6-sulfates:

composed of D-glucuronate (GlcA) and GalNAc-4- or 6-sulfate; linkage is β(1,3)
(the figure contains GalNAc 4-sulfate)
Structure of the disaccharide component of heparins

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
Structure of the disaccharide component of keratan sulfates

Keratan sulfates:

composed of galactose plus GlcNAc-6-sulfate; linkage is β(1,4)

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Characteristics of GAGs

GAG Localization Comments
Hyaluronate synovial fluid, articular cartilage, skin, vitreous humor, ECM of loose connective tissue large polymers; molecular weight can reach 1 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
Chondroitin sulfate cartilage, bone, heart valves most abundant GAG; usually associated with protein to form proteoglycans; 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
Heparan sulfate 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 GPI-linked glypicans; HSPG binds numerous ligands such as fibroblast growth factors (FGFs), vascular endothelial growth factor (VEGF), and heptocyte growth factor (HGF); HSPG also binds chylomicron remnants at the surface of heptocytes; HSPG derived from endothelial cells act as anti-coagulant molecules
Heparin 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 in vivo is likely defense against invading bacteria and foreign substances
Dermatan sulfate skin, blood vessels, heart valves, tendons, lung was originally referred to as chrondroitin sulfate B which is a term no longer used; may function in coagulation, wound repair, fibrosis, and infection; excess accumulation in the mitral valve can result in mitral valve prolapse
Keratan sulfate cornea, bone, cartilage aggregated with chondroitin sulfates usually associated with protein forming proteoglycans; keratan sulfate proteoglycans include lumican, keratocan, fibromodulin, aggrecan, osteoadherin, and prolargin

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Virtually all cells in the human body synthesize the hyaluronans. As tissues expand and cells need to migrate, the synthesis of hyaluronans increases. Indeed, hyaluronans have essential roles in development, tissue organization, cell proliferation, and signal transduction processes.

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. There are three members of the mammalian HAS gene family, HAS1, HAS2, and HAS3. These genes code for homologous proteins predicted to contain five to six membrane-spanning segments and a central cytoplasmic domain. Unlike all the other GAGs, hyaluronans are synthesized at the inner surface of the plasma membrane in eukaryotic cells. This mode of synthesis allows for the extrusion of long polymers into the ECM. These hyaluronan polymers are typically on the order of 104 disaccharides in length that exceed 3,000,000 Daltons in mass. The HAS1 gene is located on chromosome 19q13.4 and is composed of 5 exons that generate two alternatively spliced mRNAs resulting in two isoforms of the enzyme. The HAS2 gene is located on chromosome 8q24.12 and is composed of 7 exons that encode a protein of 552 amino acids. The HAS3 gene is located on chromosome 16q22.1 and is composed of 8 exons that generate three alternatively spliced mRNAs that together encode two distinct isoforms of the enzyme. The HAS3 encoded protein is thought to function as a regulator of hyaluronan synthesis as opposed to being involved directly in their synthesis.

Hyaluronan function is, in most cases, dependent upon an interaction with proteins present on the surface of the cell and/or secreted into the extracellular matrix (ECM). Hyaluronan-binding proteins were initially discovered in cartilage and this family of proteins is now called the link module family of hyaladherins. ECM linking proteins are necessary for stabilizing proteoglycan aggregates. The various link module proteins contain two motifs, the link module, that specifically interacts with hyaluronan and, as a result, forms the backbone upon which proteoglycan aggregates assemble. This particular proteoglycan is now called aggrecan (see below). The second motif in the link module protein locks the proteoglycan on the hyaluronan chain. Absence of hyaladherins leads to failure in the anchoring of proteoglycans, resulting in defects in cartilage development and delayed bone formation (short limbs and craniofacial anomalies). In addition to aggrecan-type proteoglycans, the versicans, brevicans, and neurocans also consist of a protein core that contains a link domain molecule allowing for, and necessary for hyaluronan interaction.

Hyaluronans are also critical components of complex signal transduction processes. The protein, CD44 (Indian blood group antigen), contains a cytoplasmic domain, a transmembrane domain, and an extracellular domain that contains a single link module that can bind hyaluronans. When CD44 interacts with hyaluronan it alters the activity of CD44 such that the cytoplasmic domain interacts with regulatory and adaptor molecules, such as SRC kinases, GTPases that regulate the RHO family of monomeric G-proteins, a GRB2-associated binding protein (GAB1), and proteins that regulate cytoskeletal assembly/disassembly and cell migration (ankyrin and ezrin). Hyaluronan binding to other transmembrane signaling proteins (such as HMMR: hyaluronan-mediated motility receptor; also known as RHAMM) results in the activation of the kinases, PKC, SRC, ERK1/2, and FAK (focal adhesion kinase). These kinases are involved in the regulation of cell growth and motility. Given that these hyaluronan-activated pathways are relevant to tumor cell survival and invasion, drugs that interfere with the interactions may represent novel therapeutic approaches for treating cancer.

Following synthesis, the hyaluronans can be remodeled and/or catabolized. Hyaluronic acid occurs rapidly in most tissues, taking as little as one day in most epidermal tissues. Dispite the rapid turnover, the life-time of hyaluronans can be quite long, somewhat determined by tissue and location. For example, hyaluronans in cartilage have very long life-spans. Humans express a family of hyaluronan catabolizing enzymes referred to as the hyaluronidase (HYAL) gene family. The HYAL family is composed of six genes with hyaluronidase-like sequence identity. These six genes are clustered into two sets of three contiguous genes located on two different chromosomes. Although these enzymes are referred to as hyaluronidases, several members of the family also have a limited ability to degrade chondroitins and chondroitin sulfates. All of the human hyaluronidases are endo-β-N-acetyl-hexosaminidases. In addition, these enzymes have the ability to cross-link hyaluronic acid to chondroitins and chondroitin sulfates, an activity referred to as transglycosidase. The human HYAL genes are identified as HYAL1, HYAL2, HYAL3, HYAL4, SPAM1/PH-20, and a pseudogene identified as PHYAL1.

The hyaluronidases, HYAL1 and HYAL2, have major roles in the degradation of hyluronic acid in most somatic tissues. HYAL3 has also been shown to exhibit hyaluronidase activity in somatic tissues, but also may serve an importnat role in sperm function. HYAL4 has not been shown to exhibit hyaluronidase activity but it appears that, despite its amino acid homology to the other hyaluronidases, the enzyme is a chondroitinase. The SPAM1 (also called PH-20 hyaluronidase) encodes the protein identified as sperm adhesion molecule 1. The SPAM1 encoded protein is a GPI-anchored enzyme found on the surface of human sperm and the inner acrosomal membrane. The SPAM1 encoded protein functions as a hyaluronidase that enables sperm to penetrate through the hyaluronic acid-rich cumulus cell layer surrounding the oocyte, it is a receptor involved in hyaluronic acid induced cell signaling, and is also a receptor involved in sperm-zona pellucida adhesion. The PHYAL1 gene is a transcribed pseudogene but the resulting RNA is not translated into protein.

The HYAL1, HYAL2, and HYAL3 genes are clustered on chromsome 3p21. The HYAL4 and SPAM1 genes are clustered on chromosome 7q31.3. The HYAL1 gene is composed of 7 exons that generate four alternatively spliced mRNAs. The HYAL2 gene is composed of 6 exons that generate two alternatively spliced mRNAs both of which encode the same 473 amino acid protein. The HYAL3 gene is composed of 5 exons that generate five alternatively spliced mRNAs. The HYAL4 gene is composed of 8 exons that encode a 481 amino acid protein. The SPAM1 gene is composed of 10 exons that generate five alternatively spliced mRNAs that together encode two distinct isoforms of the enzyme.

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Heparin and Heparan Sulfates

Heparin and heparan sulfates are initially composed of GlcNAc and glucuronic acid (GlcA) disaccharide units. Following formation of the disaccharide unit it undergoes extensive modifications. Both disaccharide units are sulfated with heparins being more highly sulfated than heparan sulfates. Heparin is produced solely as serglycin proteoglycan (see below in Proteoglycans section) by connective-tissue associated mast cells, whereas heparan sulfates are made by virtually all cells of the body. As this family of GAG chains polymerizes, the sugars undergo a series of modification reactions. These modifications are carried out by an epimerase and at least four families of sulfotransferases. Some GlcA residues are sulfated which blocks the epimerization reaction of glucuronate to iduronate. As indicated, during synthesis heparin becomes more sulfated than heparan sulfates and also there is a higher degree of GlcA epimerization to iduronic acid in heparins than in heparan sulfates. In heparin, more than 80% of the GlcNAc residues are N-deacetylated and N-sulfated and more than 70% of the GlcA is epimerized to iduronic acid. The sulate modification reaction in heparins and heparan sulfates occurs in clusters along the polymerized disaccharide units. This gives rise to segments referred to as N-acetylated (NA), N-sulfated (NS), and mixed domains (NA/NS). 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. Heparan sufates are found associated with three types of core proteins forming various types of proteoglycans. The syndecans, of which there are four different genes, are the most abundant forms of core proteins forming heparan sulfate proteoglycans (HSPGs). The syndecans carry heparan sulfate chains primarily near the N-terminus of the core protein. The second class of core proteins that carry heparan sulfates are the glypicans of which there are six genes. The glypicans are so-called because the core protein is tethered to the plasma membrane via a glyosylphosphatidylinositol (GPI) linkage. Both the syndecans and the glypicans can be released from the plasma membrane via proteolysis releasing biologically active HSPGs into the circulation. The third class of HSPG core protein consists of perlecan, agrin, and collagen XVIII.

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Keratan Sulfates

Keratan sulfates are composed of a highly sulfated poly-N-acetyllactosamine chain. The poly-N-acetyllactosamine structure of keratan sulfates is the same as that found attached to many glycoproteins of the N-linkage family as well as the mucins which are members of the O-linkage family of glycoproteins. Humans produce two distinct types of keratan sulfates which are defined by the nature of their linkage to protein in proteoglycans. The major core proteins to which keratan sulfates are attached in forming proteoglycans are member of the small leucine-rich repeat proteins (SLRPs). The SLRP proteins are divided into four subclasses with the class II and class III SLRPs having been found to be deocrated with keratan sulfates. Type I keratan sulfate (KS I) was originally characterized from the cornea. KS I is linked to a protein core encoded by the KERA gene. The linkage of keratan sulfate to the KERA protein is via an N-asparaginyl glycosidic linkage forming the protepoglycan called keratocan. KS II represents a skeletal form of keratan sulfate and it is bound to the core protein via an O-linkage to Ser or Thr via linkage first to GlcNAc. Within the cornea KS I proteoglycans maintain the even spacing of type I collagen fibrils which allows for photons of light to pass through the cornea without scattering. 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). In patients with CNA2 the cornea lacks the normal convex shape which prevents the correct refraction of light through the lens. Defective sulfation of keratan sulfates causes macular corneal dystrophy and defects in keratan sulfate chain formation result in keratoconus.

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Chondroitin Sulfates

The typical chondroitin sulfate disaccharide unit in humans is composed of GalNAc and GlcA, both of which can be highly sulfate modified. Chondroitin sulfate GAGs are polymerized into long chains. The incorporation of sulfur into the chondroitin sulfate sugars is a highly complex process involving multiple sulfotransferases, as is the case for the other types of sulfated GAGs. Many chondroitin sulfate chains are hybrid structures that contain more than one type of chondroitin disaccharide unit. Dermatan sulfates (see next section) are a subtype of chondroitin sulfates that contain one or more iduronic acid-containing disaccharide units. This form of the GAG is sometimes referred to as chondroitin sulfate B. Chondroitin sulfates that contain glucuronic acid in the disaccharide units instead of iduronic acid are referred to as chondroitin sulfates A and C. Chondroitin sulfates, as well as dermatan sulfates, are found attached to a large family of proteoglycan core proteins referred to as lecticans. The lectican family includes aggrecan, brevican, neurocan, and versican. In addition to chondroitin sulfates and dermatan sulfates, the aggrecans and neurocans can also be found to be carrying keratan sulfates dependent upon the tissue source.

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Dermatan Sulfates

Dermatan sulfates in humans are composed of repeating disaccharide units of iduronic acid and GalNAc. The name of this class of GAG is derived from the fact that they represent the predominant GAG in the skin (dermis). Although the presence of GalNAc technically identifies dermatan sulfate as a chondroitin sulfate, the presence of the iduronic acid establishes the deramatan sulfates as a distinct class of GAG other chondroitin sulfates. Dermatan sulfates and dermatan sulfate proteoglycans (DSPG) are responsible for the binding of numerous proteins that are involved in the modulation of a large range of physiological processes. A critical and clinically relevant example being the fact that dermatan sulfates bind to heparin cofactor-II, thrombin, and activated protein C (aPC) and in so doing regulate specific functions of the hemostasis cascade. Dermatan sulfates also interact with numerous growth factors, such as members of the fibroblast growth factor family (e.g. FGF-2 and FGF-7), thereby playing a role in the regulation of cell proliferation. The proteoglycan, decorin, is a DSPG that is important for the binding of collagen and fibronectin. The interaction between decorin and these ECM proteins serves to function as a regulator of wound repair and skin strength.

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The majority of GAGs in the body are linked to core proteins, forming proteoglycans (also called mucopolysaccharides). The GAGs extend perpendicularly from the core in a brush-like structure. The linkage of GAGs to the protein core, in most but not all proteoglycans, involves a specific tetrasaccharide linker composed of a glucuronic acid (GlcA) residue, two galactose (Gal) residues, and a xylose (Xyl) residue forming a structure such as: GAG(n)–GlcA–Gal–Gal–Xyl–Ser–protein. The tetrasaccharide linker is coupled to the protein core through an O-glycosidic bond to a Ser or Thr residue in the protein. The tetrasaccharide linker is most commonly seen in proteoglycans that contain heparins, heparan sulfates, dermatan sulfates, and chondroitin sulfates. Although most common, some GAGs are linked to the protein core of proteoglycans via a trisaccharide linkage that lacks the GlcA residue. In the case of the keratan sulfates, attachment of the sugar linker to the core protein can occur via O-linkage or via N-linkage. 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.

The protein cores of proteoglycans are rich in Ser and Thr residues, which allows multiple sites of polymeric GAG attachment. Following the formation of the tetrasaccharide linker if the next sugar added is N-acetylglucosamine (GlcNAc) the resulting attached GAGs will be either heparins or heparan sulfates. If the next sugar is N-acetlygalactosamine (GalNAc) instead, then the attached GAGs will be either chondroitin sulfates or dermatan sulfates.

Structure of major tetrasaccharide linker that couples GAG to protein in proteoglycans

Structure of the GAG linkage to protein in proteoglycans. The majority of GAGs linked to protein to form a proteoglycan are attached via a tetrasaccharide linker that consist of GlcA–Gal–Gal–Xyl–Ser residue in the protein core. This is true for most, but not all, heparin, heparan sulfate, chondroitin sulfate, and dermatan sulfate polymers attached to proteins in proteoglycans.

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 overall composition of a given type of ECM will ultimately determine the physical characteristics of the tissues it surrounds and also the many biological properties of the cells embedded in it. The proteoglycans found in the ECM interact with other ECM components keeping the level of fluidity high (forming a hydrated gel-like composition) and providing resistance to compressive forces. Different cell types produce different types of membrane-associated proteoglycans. Membrane proteoglycans have either a single membrane-spanning domain (a type I orientation) or they are linked to the membrane via a glycosylphosphatidylinositol (GPI) anchor. In addition, in some cells the proteoglycans are concentrated within secretory vesicles along with the other vesicle components. The role of vesicle proteoglycans is to help sequester and regulate the availability of positively charged vesicle components (e.g. proteases and bioactive amines such as neurotransmitters) via their interactions with the negatively charged polymeric GAG chains.

There exists a huge variability of proteoglycans in human tissues and cells. This variability is due to several factors including the large numbe of different proteoglycan core proteins and the ability add one or two different types of polymeric GAG chains to the protein core. Some proteoglycans contain only one GAG chain (e.g., decorin), whereas others can have several hundred GAG chains (e.g., aggrecan). Proteoglycan variability also results from the stoichiometry of GAG chain substitution. As an example, the proteoglycan, syndecan-1, has five attachment sites for GAGs, but not all of the sites are used equally. Another level of variability results from the fact that different cell types produce proteoglycans, from the same protein core, that exhibit differences in the number of GAG chains, the GAG chain polymeric length, and the arrangement of sulfated residues within the GAG chain.

The various proteoglycans have been divided into several major classes which are defined by their function, tissue distribution, and protein homologies. The major classes include the interstitial proteoglycans, the basement membrane proteoglycans, the secretory granule proteoglycans, and the membrane-bound proteoglycans.

Interstitial Proteoglycans

Interstitial proteoglycans are present in the ECM, and their distribution depends on the nature of the ECM. The interstitial proteoglycans represent a highly diverse class of molecules that differ in size and GAG composition. The majority of interstitial proteoglycans are small leucine-rich proteoglycans (SLRPs). The protein cores of SLRPs contain leucine-rich repeats flanked by cysteines in their central domain. To date there are nine members of the SLRP family of proteoglycans. The SLRPs have been shown to contain chodroitin sulfates, dermatan sulfates, and keratan sulfates. Interstitial proteoglycans are critical components in the ECM involved in the stabilization and organization of collagen fibers. The SLRPs are abundant within tendons. Within the cornea, keratan sulfate-containing SLRPs maintain the register of collagen fibers that is required for the transparency of the cornea.

The lectican family (also referred to as the aggrecan family) of interstitial proteoglycans consists of aggrecan, brevican, neurocan, and versican. All four members of this proteoglycan family contain a unique protein core and each core protein contains an amino-terminal domain that can bind hyaluronans, a central domain to which chondroitin sulfates and dermatan sulfates are attached, and a carboxy-terminal domain that contains a C-type lectin domain. The core protein of aggrecan is encoded by the ACAN gene. The core protein of brevican is encoded by the BCAN gene. The core protein of neurocan is encoded by the NCAN gene. The core protein of versican is encoded by the VCAN gene. Aggrecan itself is the most well characterized member of aggrecan family and is the major proteoglycan in cartilage. Aggrecan can contain upwards of 100 chondroitin sulfate chains and can also contain keratan sulfate chains dependent upon the tissue of synthesis. Neurocan is produced in the late embryonic central nervous system (CNS) and can inhibit neurite outgrowth. Brevican is produced in the terminally differentiated CNS. Versican is produced predominantly by connective tissue cells. 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. Versicans have major roles in neural crest cell and axonal migration.

Basement Membrane Proteoglycans

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. The basement membrane is found flush against epithelial cells. It is composed primarily of laminin, nidogen, collagens, and proteoglycans. There are at least four different types of proteoglycan found within basement membranes. These proteoglycans are perlecan, agrin, collagen type XVIII, and leprecan. The GAG chains in perlecan, agrin, and type XVIII collagen are heparan sulfates. The GAG chains in leprecan are chondroitin sulfates, however, some forms of perlecan have also been shown to contain chondroitin sulfates. Perlecan is also known heparan sulfate proteoglycan (HSPG) of basement membrane. Leprecan is also known as leucine proline-enriched proteoglycan. The protein core of perlecan is encoded by the HSPG2 gene. The protein core of agrin is encoded by the AGRN gene. The protein core of leprecan is encoded by the LEPRE1 gene. Perlecan is composed of multiple domains that have different functions. Perlecan has been shown to play a role in embryogenesis, tissue morphogenesis, and cartilage development. Agrin is so-called since it was originally characterized at neuromuscular junctions where it is responsible for the aggregation of acetylcholine receptors. Agrin is also functional in renal tubules where its role is in the determination of the filtration properties of the glomerulus.

Secretory Granule Proteoglycans

The major secretory vesicle proteoglycan is serglycin. Serglycin is also known as hematopoietic proteoglycan. The core protein of serglycin is encoded by the SRGN gene. Serglycin is the major proteoglycan found in cytoplasmic secretory granules within endothelial, endocrine, and hematopoietic cells. Serglycin contains a variable number of GAG attachment sites to which either heparin chains or chondroitin sulfate chains are attached. Heparin, a more highly sulfated form of heparan sulfate, is made exclusively on serglycin that is produced in mast cells associated with connective tissue. Although there are other secretory proteoglycans (e.g. chromogranin A) these have only been shown to be part-time proteoglycans.

Membrane-Bound Proteoglycans

The family of membrane proteoglycans is quite diverse and consists of the syndecans and the glypicans in addiiton to several other proteoglycan forms. The syndecan family consists of four members, syndecan-1, -2, -3, and -4. Each of the protein cores of the syndecans contains a short hydrophobic domain that spans the membrane, a large extracellular domain that contains the GAG attachment sites, and a smaller intracellular cytoplasmic domain. Syndecan-1 and syndecan-3 have chondroitin sulfate chains attached to the protein core near the membrane-spanning domain and heparan sulfate chains attached to the more distal sites of the core protein. Syndecan-2 and syndecan-4 have only heparan sulfate chains attached to the protein core. The syndecans are expressed in a tissue-specific manner where they are involved in the regulation and facilitation of cellular interactions with ECM molecules and extracellular growth factors and matrix molecules. The syndecans also are involved in the transmission of signals from the extracellular environment to the intracellular cytoskeletal architecture through their cytoplasmic tails. Because of their membrane-spanning properties, the syndecans can transmit signals from the extracellular environment to the intracellular cytoskeleton via their cytoplasmic tails. The syndecans, like most proteoglycans can, and do, undergo remodeling. In addition, matrix metalloproteases cleave off portions of the extracellular domains of the syndecans resulting in the shedding of what are referred to as ectodomains. The syndecan ectodomains harbor the GAG chains and exhibit potent biological activities on their own.

The glypicans also represent a unique family of membrane-bound proteoglycans. There are six glypican family members in mammals idendified as glypican-1 (GPC1) through GPC6. Each of the glypicans is tethered to the plasma membrane via a GPI anchor which is attached at the carboxyl terminus of the protein core. Because of the GPI linkage to the plasma membrane, glypicans do not possess an intracellular cytoplasmic tail like the syndecans. The N-terminal domains of the glypicans fold into globular structures which is another feature that distinguishes this family from the syndecan family. The N-terminal domains of the glypicans also contain multiple Cys residues. Glypican proteoglycans carry only heparan sulfates as the attached GAGs.

Glypican-3 (GPC3) is the most well characterized and studied glypican. This is primarily due to the fact that humans that harbor mutations in the GPC3 gene suffer from Simpson-Golabi-Behmel syndrome (SGBS), characterized as an overgrowth disorder. This syndrome is characterizerd by distinctive facial features that includes hypertelorism (widely spaced eyes), macrostomia (unusally large mouth), macroglossia (large tongue), abnormal palate, and a broad upturned nose. This constellation of facial features is commonly referred to as coarse facies or coarse facial features. For this reason it is important that the underlying cause be correctly diagnosed as many inherited disorders in metabolism result in the appearance of coarse facies. In addition to the facial abnormalities, infants with SGBS have chest and abdominal abnormalities, including one or more extra nipples, diastasis recti (abnormal opening in the abdominal muscles), umbilical heriation, or a diaphragmatic hernia (a hole in the diaphragm). Internally there are additional features of SGBS that include heart defects, malformed or abnormally large kidneys, hepatosplenomegaly, and skeletal abnormalities.

Representative Mammalian Proteoglycan Types

Proteoglycan Comments
Aggrecan 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
Brevican 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
Decorin 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
Keratocan 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
Lumican 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
Neurocan 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
Perlecan 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)
Syndecans 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 tumour 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
Versican 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

Structure of an aggrecan type complex proteoglycan

Structure of an aggrecan-type complex proteoglycan

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Clinical Significances of Glycosaminoglycan Degradation

Proteoglycans and GAGs perform numerous vital functions within the body, some of which still remain to be studied. One well-defined function of the GAG heparin is its role in preventing coagulation of the blood. Heparin is abundant in granules of mast cells that line blood vessels. The release of heparin from these granules, in response to injury, and its subsequent entry into the serum leads to an inhibition of blood clotting, in the following manner. Free heparin complexes with and activates antithrombin III, which in turn inhibits all the serine proteases of the coagulation cascade. This phenomenon has been clinically exploited in the use of heparin injection for anti-coagulation therapies.

Several genetically inherited diseases, for example the lysosomal storage diseases, result from defects in the lysosomal enzymes responsible for the metabolism of complex membrane-associated GAGs. These specific diseases are termed the mucopolysaccharidoses (MPS) in reference to the historical term, mucopolysaccharide, used to describe the glycosaminoglycan-protein complexes called proteoglycans. The various MPS lead to an accumulation of GAGs within lysosomes of affected cells. There are at least 14 known types of lysosomal storage diseases that affect GAG catabolism; some of the more commonly encountered examples are indicated in the Table below. All of these disorders, excepting Hunter's syndrome (X-linked recessive), are inherited in an autosomal recessive manner. To see a diagram of the locations of the enzyme defects in GAG degradation go to the Mucopolysaccharidoses page.

Type: Syndrome Enzyme Defect Affected GAG Symptoms
α-L-iduronidase dermatan sulfate, heparan sulfate corneal clouding, dysostosis multiplex, organomegaly, heart disease, dwarfism, mental retardation; early mortality
α-L-iduronidase dermatan sulfate, heparan sulfate corneal clouding; aortic valve disease; joint stiffening; normal intelligence and life span
α-L-iduronidase dermatan sulfate, heparan sulfate intermediate between I H and I S
L-iduronate-2-sulfatase dermatan sulfate, heparan sulfate mild and severe forms, only X-linked MPS, dysostosis multiplex, organomegaly, facial and physical deformities, no corneal clouding, mental retardation, death before 15 except in mild form then survival to 20 - 60
Sanfilippo A
heparan N-sulfataseheparan sulfate profound mental deterioration, hyperactivity, skin, brain, lungs, heart and skeletal muscle are affected in all 4 types of MPS-III
Sanfilippo B
α-N-acetyl-D-glucosaminidase heparan sulfate phenotype similar to III A
Sanfilippo C
acetylCoA:α-glucosaminide-acetyltransferase heparan sulfate phenotype similar to III A
Sanfilippo D
N-acetylglucosamine-6-sulfatase heparan sulfate phenotype similar to III A
Morquio A
galactose-6-sulfatase keratan sulfate, chondroitin 6-sulfate corneal clouding, odontoid hypoplasia, aortic valve disease, distinctive skeletal abnormalities
Morquio B
β-galactosidase keratan sulfate severity of disease similar to IV A
MPS V, a designation no longer used
arylsulfatase B
also called N-acetylgalactosamine-4-sulfatase
dermatan sulfate 3 distinct forms from mild to severe, aortic valve disease, dysostosis multiplex, normal intelligence, corneal clouding, coarse facial features
β-glucuronidase heparan sulfate, dermatan sulfate, chondroitin 4-, 6-sulfates hepatosplenomegaly, dysostosis multiplex, wide spectrum of severity, hydrops fetalis
MPS VIII, a designation no longer used

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Last modified: August 17, 2016