Hyaluronan‐protein interactions: Lilliput revisited

Abstract Hyaluronan (HA) is a huge linear polysaccharide composed entirely of a simple repeating disaccharide that has been preserved unchanged since the evolution of vertebrates ~520 million years ago. It is present in all mammalian tissues, being synthesised within the cell membrane and extruded into the extracellular space where it dictates tissue elasticity, hydration and permeability. HA also directs cell behaviour via engagement with cell surface receptors. These properties allow it to mediate diverse functions in a wide range of physiological and pathological processes, including development, mammalian reproduction and inflammation. There is growing evidence that the way in which the HA biopolymer is differentially organised, through its interaction with a repertoire of HA‐binding proteins (HABPs), is key to the diversity of its biological functions. This review summarises current knowledge of HA‐protein interactions and how their diversity may lead to the formation of HA/protein complexes with distinct molecular architectures that in turn underpin different physical properties and receptor‐mediated effects. Potentially controversial areas such the pro‐inflammatory effects of low molecular weight HA fragments and how short HA‐binding peptides modulate HA function are considered from a molecular perspective.