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Carbohydrate binding: CD44 switches conformation

Comparison of the molecular surface of crystal complex A (gold carbons) and crystal complex B (green carbons).

The polysaccharide hyaluronan (HA) interacts with the transmembrane adhesion molecule CD44 to regulate tumor development and inflammation. HA is a glycosaminoglycan composed of glucuronic acid and N–acetylglucosamine that makes up a large part of the extracellular matrix. CD44 binds HA through a structural feature called the 'Link module'. The tertiary conformation of the Link module has been previously determined, and now in Nature Structural and Molecular Biology Banerji et al. expand on this by describing the crystal structure of the CD44-HA binding complex.

The authors analyzed a crystallized complex of HA octasaccharide (HA8) and a fragment of the murine CD44 protein (CD44_25-174). They showed that this complex exists in two stable conformations, type A and type B. The conformation of type A resembles CD44 apoprotein, while type B builds closer contacts with HA8. In both conformation types, CD44 only recognized HA8 glycan residues 5-8 to form the binding complex.

The HA binding domain of the CD44 Link module has thirteen amino acid residues that make contact with the octasaccharide. Based on their crystallographic data the authors propose that CD44 recognizes HA by its hydrogen bonds and van der Waals forces. This model stands in contrast to previous observations from site-directed mutagenesis that suggests that it is the sugar-aromatic stacking interactions that contribute to the HA-binding specificity of CD44. Instead of stacking interactions, Banerji et al. show that the aromatic amino acids neighboring bound HA form hydrogen bonds with the octasaccharide.

HA-bound CD44 undergoes conformational changes around Glycine44, displacing its contact with one arginine residue and forming contact with another. In addition, the C-terminal portion of the type B form shows conformational differences to the type A form that might contribute to an increased binding strength between CD44 and HA8. Taking into account nuclear magnetic resonance data, the authors conclude that HA binding leads to a transition between the type A and type B conformations.

The results of this study mark a strong contrast to previous hypotheses about CD44–HA binding. However, the reported CD44 conformational change corresponds to a previous finding in vivo that indicates that leukocyte CD44 switches between different ligand binding affinities in response to cytokine stimulation. Given that CD44 is glycosylated, changes in CD44 glycan structure — such as desialylation — might further contribute to this affinity change. Further research in vivo may lead to the development of drugs that alter the CD44 binding behavior that could be used for the treatment of inflammatory diseases such as asthma and rheumatism.

Author: Mirko von Elstermann