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A Concise Overview: Structure and Functions of Proteoglycans
Proteoglycans are one of the major components of the extracellular matrix; they act as fillers between the spaces that occur between cells. This BiologyWise post gives information on the structure of proteoglycans and its various functions in bones, cartilages, etc.
Protein that Acts Like a Carbohydrate!
Glycosaminoglycans make about 95% of the weight of proteoglycans; due to this, proteoglycans resemble more of polysaccharides rather than proteins.
The extracellular matrix functions in holding all the cells of a tissue in their place. Its composition depends on the cell secreting it. The extracellular matrix consists of two major substances: ground substances and fibrous proteins. Proteoglycans are a type of ground substances. They are either secreted in the extracellular matrix, inserted into the plasma membrane, or stored in various secretory granules.
Proteoglycans are basically a class of proteins that are heavily glycosylated. Here, the glycosaminoglycans are covalently attached to certain proteins called core proteins. These are the most abundant heteropolysaccharides that are present in the body. These proteins are synthesized in the rough endoplasmic reticulum, further modified in the golgi body, and are finally transported to the extracellular matrix by vesicles.
Structure of Proteoglycans
Proteoglycans are composed of two basic molecules, core protein and glycosaminoglycans. The core protein may contain serine residues; these residues act as a point of attachment to which different glycosaminoglycans attach. The glycosaminoglycans attach to the core proteins perpendicularly and give rise to a brush-like structure. Their attachment in most but not all proteoglycans is through a tetrasaccharide linker that consist of glucuronic acid(GlcA), two galactose(Gal) and a xylose(Xyl) residue via glycosidic bonds. And some glycosaminoglycans are linked to the protein core of proteoglycans through a trisaccharide linkage that lacks the GlcA residue.
The core proteins are highly conserved in the animal kingdom. These proteins are rich in amino acids such as serine and threonine. Glycosaminoglycans are long, unbranched molecules that contain repeating disaccharide units of a uronic acid such as glucuronic acid(GlcA) or iduronic acid. and an amino sugar (either N-acetylglucosamine, or N-acetylgalactosamine). These glycosaminoglycans impart a negative charge on proteoglycans. Different proteoglycans arise due to the different glycosaminoglycans that are attached to it.
Proteoglycans can be classified on the basis of glycosaminoglycans they possess. There are four basic types of glycosaminoglycans: chondroitin sulfate (CS), heparan sulfate, dermatan sulfate (DS), and keratan sulfate (KS). These glycosaminoglycans give rise to a number of proteoglycans like decorin, biglycan, aggrecan, neurocan, testican, fibromodulin, lumican, etc.
Proteoglycans form large complexes with other proteoglycans, fibrous proteins (like collagen), and other components (hyaluronan) of the extracellular matrix.
Diverse Functions of Proteoglycans
Proteoglycans in Cartilage
The extracellular matrix of cartilage contains five well-characterized proteoglycans. Out of all the proteoglycans present, aggrecan is the most abundant. It has more than hundred chondroitin sulfates and keratan sufaltes. They interact with molecules of hyaluronan to form large aggregates. Aggrecan provides cartilage with the property to bind with water to form hydrated matrices. These molecules act as fillers between the cell spaces.
They are present in the cartilage and form aggregates with hyaluronan. They help to form a matrix that is stable and is capable of withstanding high compressive forces without changing its shape. They do this either by desorption or absorption of water. Other closely related proteoglycans like decorin, biglycan, and fibromodulin are present too. Decorin and biglycan contain one and two chains of DS, respectively. Fibromodulin, on the other hand, possesses several chains of keratan sulfate. Decorin and fibromodulin interact with collagen fibers, stimulate fibrogenesis, and enhance the interactions between fibers. Finally, type IX collagen (a type of proteoglycan) acts as a bridge that connects collagen fibers with the surrounding aggrecan molecules.
Proteoglycans in the Bone
The bone matrix has a lower proteoglycan content than those in the cartilage. This is the reason bones take up less quantity of water and are, thus, more brittle. Bones contain small leucine-rich proteoglycans (SLRPs). Decorin and biglycan are predominantly present in bones and contain either chondroitin sufate or dermatan sulfate. These proteoglycans are required in all phases of bone development such as proliferation of cells, deposition of matrix, and mineral deposition of cells.
Biglycan is required for proper formation of collagen fibers and bone production (as bone contains 90% of collagen). Lumican is another proteoglycan found in the bone matrix; it is secreted by mature osteoblasts. Another proteoglycan called keratocan, also found in the bone matrix, is required for proper bone formation and mineralization. Other proteoglycans like epiphycan, asporin, and fibromodulin are also required for proper bone development.
Other Functions of Proteoglycans
◆ Proteoglycans, many a time, act as cell surface receptors for different enzymes or their inhibitors. Some proteoglycans that are present in the extracellular matrix may bind to different cytokines, growth factors, and other compounds and prevent their degeneration by proteases.
◆ They can act as endocytic receptors for the clearance of bound ligands.
◆ They cooperate with proteins such as integrins and facilitate cell migration, cell-cell interactions, and cell attachment.
◆ Some proteoglycans play a role in the regulation of certain biological processes like coagulation, wound repair, host defenses, and cellular packaging.
◆ They bind to cations such as sodium, potassium, and calcium, as well as water, and help in regulating the movement of molecules through the matrix.
◆ Some proteoglycans either due to the core protein or the attached glycosaminoglycan chains can serve as lubricants.
◆ Proteoglycans are required for the organization of the basement membrane and play an important role in cell proliferation and differentiation. They can also regulate the cell permeability in certain specialized basement membranes.
The recent understanding of the role of proteoglycans in development, stem cells, cancer, cardiovascular diseases, etc., have inspired attempts to engineer an array of drugs that either function like proteoglycans or target proteoglycans for their activity.