Series Introduction: Heparan sulfate proteoglycans: intricate molecules with intriguing functions

Abstract

Heparan sulfate proteoglycansThe term heparan sulfate proteoglycan (HSPG) refers to a dichotomous structure, a protein coupled to a unique glycosaminoglycan chain characterized by a linear array of alternating disaccharide units.Both the protein core and the side chains undergo a series of modification reactions, which endow them with a very complex fabric (1).The final product is a sophisticated compound that can fluctuate in size, fine structure, and biology (2-5).The complexity of a usual heparan sulfate chain, for instance, can easily surpass that of common nucleic acids (6, 7).The field of proteoglycan research is nearly equally split into two factions: those who feel that heparan sulfate is the prima donna, with the protein core being just a carrier, and those who feel that there would be no role for heparan sulfate without the protein core.The truth, as usual, is in the middle.Both possess unique features that in some respects act synergistically to provide the maximal strength of signaling and biological activity.This Perspective series, motivated by the recent flurry of discoveries, has been coordinated to provide a balanced view of the most recent advances in the field of HSPG research.The development of novel experimental strategies for decoding the sequence of heparan sulfate (8-10), together with the availability of antibodies specific for heparan sulfate epitopes (11), holds promise for deciphering the functional specificity of heparan sulfate in tissues.The medical importance is underscored by the direct involvement of HSPGs in various human diseases involving the musculoskeletal system, such as the Schwartz-Jampel chondrodystrophic myotonia (12) and the dyssegmental dysplasia Silverman-Handmaker type (13), overgrowth syndrome (Simpson-Golabi-Behmel) (14), or hereditary bone disorders (hereditary multiple exostoses) (15). A few take-home messagesThe heparan sulfate chains vary in length from ∼5 to ∼70 kDa.This is an important and often forgotten point.Glycosaminoglycan chains, joined to the polypeptide, also enjoy ample freedom to move laterally.These linear polymers can reach distant targets that can be located several hundreds of nanometers