Proteoglycans are complex extracellular macromolecules consisting of a multidomain core protein to which are attached one or more glycosaminoglycan (GAG) chains. They are structurally very diverse, due to variations in length and sequence of the core proteins as well as abundance, distribution and composition of the GAG chains. Core proteins are often arranged in modules which have structural and functional significance, and the same module may be found in more than one core protein type. A single core protein type may have different GAG substituents and differing roles in different tissues. Proteoglycans have diverse, but often vital functions in a variety of tissue context. Genetic studies of proteoglycan core proteins and their modifying enzymes have elucidated numerous heritable diseases and syndromes. Much of our understanding of the structure, function, evolution, gene regulation and mutations causing heritable disorders of proteoglycans, in general, derives from the model proteoglycan, aggrecan.

Key Concepts

• Glycosaminoglycans are linked to proteoglycan core proteins via a limited number of O- or N-glycosyl bonds.
  
• Synthesis of GAG chains proceeds by the sequential action of glycosyltransferases that catalyse transfer of a glycosyl unit from a nucleotide sugar to a protein or nonreducing end of a sugar acceptor.
  
• Proteoglycans are abundant components of the extracellular matrix and associated with the cell surface.
  
• Although there are only six major classes of proteoglycan types, there is great diversity in structure, size and composition.
  
• Important functions have been attributed to both the protein backbone and glycosaminoglycan substituents.
  
• Proteoglycans modulate numerous molecular interactions, for example, cell–cell signalling.
  
• Heritable proteoglycan disorders cause a wide range of phenotypes with examples from all clinical specialities.