Heparan sulfate (HS) is a complex carbohydrate found in all animal tissues. It belongs to a larger family of molecules known as glycosaminoglycans (GAGs), which are long chains of sugars that often carry a negative charge. HS rarely exists as a free molecule; instead, it is typically attached to specific proteins, forming what are called heparan sulfate proteoglycans (HSPGs). These proteoglycans are present in virtually every cell and tissue, acting as versatile players in various biological processes.
Structure and Distribution
Heparan sulfate is a linear polysaccharide built from repeating disaccharide units, which are pairs of sugar molecules. The most common disaccharide unit consists of glucuronic acid linked to N-acetylglucosamine. These units can undergo various modifications, including sulfation, which contribute to the molecule’s diverse structure. The addition of sulfate groups gives HS its characteristic negative charge.
These HS chains are covalently linked to specific core proteins, forming heparan sulfate proteoglycans (HSPGs). There are several classes of HSPGs, including transmembrane syndecans and glycosylphosphatidylinositol (GPI)-anchored glypicans, which are found on the cell surface. Other HSPGs, such as perlecan and collagen XVIII, are found within the extracellular matrix, the intricate network surrounding cells. This widespread distribution highlights HS’s pervasive influence throughout the body.
Diverse Biological Functions
Heparan sulfate interacts with a vast array of proteins, influencing numerous cellular and molecular events. HS can bind to a wide range of proteins including growth factors, cytokines, chemokines, enzymes, and cell adhesion molecules. The ability of HS to bind these diverse ligands is attributed to its structural variability, particularly in its sulfation patterns.
One primary role of HS is in cell signaling, where it acts as a co-receptor. It binds to growth factors like fibroblast growth factor (FGF), Wnt, and Hedgehog, facilitating their interaction with specific receptors. This interaction can enhance the affinity of growth factors for their receptors, influencing processes such as cell growth, proliferation, and differentiation.
HS is also involved in cell adhesion and migration by binding to molecules like selectins and integrins, which are crucial for cells to attach to surfaces and move within tissues. It plays a part in tissue development by helping to form gradients of signaling molecules (morphogens) that guide cell specification. HS can also act as a reservoir for regulatory factors, sequestering growth factors and cytokines in the extracellular matrix and releasing them when needed, thus fine-tuning signal transduction.
Heparan Sulfate in Health and Illness
Heparan sulfate’s widespread functions contribute to normal physiological processes, and its dysregulation can impact health. For example, HS plays a part in immune responses and inflammation, influencing the migration and activation of immune cells. Heparanase, an enzyme that degrades HS, can release various HS-bound growth factors and cytokines, which can then promote inflammation and tissue remodeling.
Abnormalities in heparan sulfate structure or function are linked to various diseases. In cancer, changes in HS sulfation patterns or the activity of heparanase can contribute to tumor progression, angiogenesis (new blood vessel formation), and metastasis. HS also serves as a cellular receptor for numerous viruses, including respiratory syncytial virus and SARS-CoV-2, influencing their attachment and entry into host cells.
HS is implicated in metabolic disorders and cardiovascular diseases due to its interactions with lipoproteins and other molecules involved in fat metabolism. Dysregulation of HS has also been associated with inflammatory disorders and kidney dysfunction, highlighting its broad impact on health.
Distinguishing Heparan Sulfate from Heparin
While heparan sulfate and heparin are both members of the glycosaminoglycan family and share structural similarities, they have distinct primary roles and distributions. Heparan sulfate is a ubiquitous component found on the surface of nearly all cell types and throughout the extracellular matrix in animal tissues. Its diverse structure allows it to participate in a wide range of biological interactions.
Heparin, in contrast, is primarily known as a pharmaceutical anticoagulant drug. It is mainly produced and stored within the secretory granules of mast cells, a specific type of immune cell. Although both molecules have anticoagulant properties, heparin’s activity is significantly higher due to its more extensive and specific sulfation patterns, particularly the presence of a unique pentasaccharide motif that binds to antithrombin.