Hyaluronan: a simple polysaccharide with structural plasticity and functional diversity

Abstract

Hyaluronan (HA) is a high‐molecular weight glycosaminoglycan that is involved in an extracellular matrix (ECM) organization and cell adhesion, essential to a wide range of normal physiological processes (e.g. development, immunology and reproduction). Its diverse biological activities may seem surprising for a simple linear polysaccharide composed solely of a repeating disaccharide of glucuronic acid and N‐acetylglucosamine. However, HA is likely to be able to take up many different conformational states, which are transient and rapidly interchanging in solution (Day & Sheehan 2001). It has been suggested that the interaction of HA with different HA‐binding proteins (hyaladherins) may stabilize particular conformations of the polysaccharide leading to HA‐protein complexes with distinct architectures and unique biological properties (Day & Sheehan 2001). Consistent with this hypothesis, recent studies on TSG‐6 (Blundell et al. 2003) and CD44 (Teriete et al. 2004) and molecular modelling of other members of the Link module superfamily reveal significant structural diversity in the HA‐binding domains in these related hyaladherins. Furthermore, there is evidence emerging that the complexes formed between polymeric HA and proteins can exhibit a wide range of higher order structures depending on the hyaladherin(s) involved. In some cases, these complexes may play mainly a structural role in ECM (e.g. the link protein/aggrecan/HA aggregates that provide load bearing function to cartilage), while in other cases they act as cell binding/activation sites (e.g. HA cables formed during inflammation). There is evidence that the function of HA can be modulated by its interaction with proteins. For example, preincubation of HA with TSG‐6 enhances/induces the binding of HA to cell surface CD44 on constitutive/inducible lymphocyte backgrounds (Lesley et al.); these activities are probably caused by the formation of cross‐linked HA fibrils that lead to receptor clustering. HA can also become modified by the covalent attachment of heavy chains (HCs), derived from the interα‐inhibitor, where TSG‐6 plays an essential role in this process (Mukhopadhyay et al.); this reaction is critical for the formation of a HA‐rich ECM required for successful ovulation and fertilization. HC‐HA complexes are also formed during inflammation but their function is not yet clear.