General Molecular Architecture
Proteoglycans differ fundamentally from most standard glycoproteins in their chemical composition: the protein portion accounts for about 5% of the mass, while the remaining 95% consists of long carbohydrate chains known as glycosaminoglycans (GAGs).
The central element of the molecule is a core protein, which consists of a single polypeptide chain (its molecular mass can vary significantly). Glycosaminoglycans are covalently attached to this core protein. Important exception: hyaluronic acid (hyaluronan) is never linked to a protein covalently.
Attachment of carbohydrate chains to the protein occurs at specific sites:
- Through the OH group of the amino acids serine or threonine (forming an O-glycosidic bond).
- Through the $NH_2$ group of asparagine (N-glycosidic bond).
A typical attachment site (using serine as an example) includes a specific linking trisaccharide: Xyl – Gal – Gal (Xylose – Galactose – Galactose). The long polysaccharide chain, composed of repeating disaccharide units (hexuronic acid and an aminosugar), is built upon this linker.
Aggrecan — The Basis of Cartilage Matrix
The best-known representative of proteoglycans is aggrecan. It is a giant molecule that serves as a major structural component of the cartilage extracellular matrix.
The core protein of aggrecan has a mass of about 220 kDa and is structurally divided into three globular domains: G1 and G2 (at the N-terminus) and G3 (at the C-terminus). Carbohydrate chains are attached primarily in the region between the G2 and G3 domains. A massive number of GAGs attach to this single protein:
- About 100 chains of long chondroitin sulfate (making up the bulk of the mass).
- About 100 chains of keratan sulfate (located closer to the N-terminus, between the G2 domain and the chondroitin sulfate region).
Supramolecular Aggregates
In the extracellular matrix, aggrecan monomers do not float individually. They assemble into colossal supramolecular complexes.
The central axis of such a complex is a long strand of hyaluronic acid. Approximately 100 aggrecan molecules bind non-covalently to it (via the G1 domain). To prevent this massive structure from falling apart, it is further stabilized by about 100 molecules of a small link protein, which anchors aggrecan to the hyaluronic acid strand.
As a result, a giant complex with a molecular mass exceeding $200 \cdot 10^6$ Daltons is formed, resembling a bottle brush, where the wire represents hyaluronic acid and the bristles represent aggrecan monomers.
Functions and Physiological Role
Proteoglycans are primarily localized in the extracellular matrix of tissues that constantly undergo mechanical deformation and high stress. These include articular cartilage, intervertebral discs, menisci, ligaments, tendons, and skin.
Due to a massive number of negatively charged groups (sulfate and carboxyl groups), glycosaminoglycans exhibit exceptionally high hydrophilicity—they attract and tightly bind water. This provides resilience and shock-absorbing functions. Under mechanical pressure, proteoglycans compress, expelling part of the water, and upon release of the load, they instantly draw the water back in, dampening impacts.
Basement Membrane Proteoglycans
A distinct and important group consists of heparan sulfate proteoglycans (HSPGs), which are key components of basement membranes.
Structurally, they are divided into two types:
- Low-density HSPGs (feature a large multi-domain core protein and three very long heparan sulfate chains).
- High-density HSPGs (feature a small core protein and four short carbohydrate chains).
HSPG molecules are strong polyanions (carrying a prominent negative charge). Due to this property, they establish a powerful electrostatic filtration barrier in the renal glomeruli that repels other negatively charged plasma molecules, preventing them from entering the primary urine.