Hyaladherins

A vertebrate homologue of the cell cycle control protein CDC37 was recently cloned and found to be an hyaladherin,62 as was a protein that copurified with the splicing factor SF2.63 An intracellular form of the HA receptor RHAMM was demonstrated to regulate erk kinase activity. Changes in function of these intracellular, depending on whether or not they have HA molecules attached, confers another layer of complexity dependent on intracellular hyaluronidase enzymes. 

The biological properties of HA in aqueous solution is controlled by reversible tertiary structures, as defined by NMR spectroscopy. Evidence suggests a ft-pleated sheet-like array stabilized by H- and hydrophobic bonds. Easy transitions between secondary and tertiary structures occur that are convenient mechanisms for switching between functions. The 20 kDa or 50-disaccharide unit is around the size at which such stable tertiary structures are expected to form.199,200 Polymers greater than 20 kDa provide the preferred substrate for Hyal-2. The enzyme cleaves at a much slower rate once the HA substrate loses tertiary structure. The hyaladherins may also provide additional substrate specificity.201 The array of hyaladherins that bind to tertiary HA structures may differ from those that bind to HA chains with exclusively secondary structure. The substrate specificity of Hyal-2 may depend on a combination of differences in bound hyaladherins and on secondary versus tertiary structure. 

In the organism, HA occurs in many diverse forms, circulating freely, decorated with a variety of HA-binding proteins (hyaladherins), tissue-associated, intercolated into the ECM by electrostatic or covalent binding to other matrix molecules. It comprises a major portion of the intimate glycocalyx that surrounds all cells. HA can be tethered to cell surfaces by any of a number of membrane-associated receptors. Recent evidence indicates that HA also exists within cells, though little is known of the form or function of such HA. 

Hyaladherins are also found intracellularly, where they may be involved in the intracellular and nuclear functions of HA. These include the cell-cycle control protein Cdc37 [26] and splicing factor... 

SF2 [27]. In some cases, it may be the hyaladherins that confer HA-specific functions, rather than the strand of HA itself... 

Glycosaminoglycans are solubilized from stromal or other tissues by extracting the source tissue with dilute acid or alkali. Hyaluronan is electrostatically bound to specific proteins called hyaladherins, which possess a structural domain of -100 amino acids termed a link module. Other glycosaminoglycans are O-linked to serine and threonine residues of polypeptides and these bonds hydrolyze before the rest of the polysaccharide. The protein moiety precipitates when trichloroacetic acid or ammonium sulfate is added to the cooled mixture. The composition of the GAGs (including hyaluronan) was identified by chromatographic separation of the purified polysaccharides, followed by their hydrolysis in boiling 1.0 M HC1 for 2 1 h and identification of the individual monosaccharide components. 

Due to this significant importance, there were many attempts to influence HA-protein interactions firstly, the overexpression of soluble hyaladherins that may displace HA completely from its endogeneous cell surface receptors [121]. Secondly, the administration of defined HA oligosaccharides that... 

Fraser et al (1972) showed 25 years ago that addition of various serum proteins to hyaluronan substantially increased the viscosity and this has received a renewed interest in view of recently discovered hyaladherins (see above). The TSG-6 and inter-a-trypsin inhibitor and other acute phase reactants such as haptoglobin are concentrated to arthritic synovial fluid [52], It is not known to what extent these are affecting the rheology and lubricating properties. 

Courel, M. N., Maingonnat, C., Tranchepain, F., Deschrevel, B., Vincent, J. C., Bertrand, R, and Delpeeh, B. (2002). Importance of hyaluronan length in a hyaladherin-based assay for hyaluronan. Analytical Biochemistry 302, 285-290. 

Hyaluronan is widely used in applied biochemistry and enzymology as a substrate for the quantitative determination of the enzyme hyaluronidase. Scientific disputes about the possible relationship between HA and hyaluronate lyase and the pathogenicity of some streptococci are to be, as it seems, permanently carried out. Currently, much attention is paid to the study of the secondary and tertiary structures and dynamic conformation of HA in aqueous solutions and biological fluids the HA interaction with proteins, particularly receptor CD44 and other hyaladherins and the HA biocatalytic cleavage with different hyaluronidase the progression toward creating of recombinant strains and chimera products with the desired properties. 

Regulator of cellular activity HA is not just an inert compound, acting as a vital structural component of connective tissues. It also plays an important role in diverse biological processes, such as cellular migration, mitosis, inflammation, cancer, angiogenesis, and fertilization. HA influences cell behavior by binding specific proteins, termed hyaladherins. Many reports have been published on the role of HA receptors [26-32]. 

Toole, B.P. Hyaluronan and its binding proteins, the hyaladherins. Curr. Opin. Cell Biol. 1990. 2, 839-864. 

Hyaluronan Binds to Several Types of Proteins (Hyaladherins j 687... 

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