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Deciphering pH-dependent Receptor Affinity

TSG-6, the secreted product of tumor necrosis factor-stimulated gene 6, is a member of the link module family of hyaluronan (HA)-binding proteins and has anti-inflammatory and protective functions in arthritis and asthma. The interaction between TSG-6 and HA is pH-dependent, with an increase in affinity between pH 3.5 and 6.0 and a reduction in affinity between pH 6.0 and 8.0. This pH-dependent interaction provides a means of differentially regulating TSG-6 activity in different tissue microenvironments.

Changes in His4 charge state are relayed to HA-binding residues via a network involving Asp89 and Tyr12.

In this Paper of the Week, Charles D. Blundell and colleagues investigated the mechanism underlying this pH dependence using a combination of site-directed mutagenesis, nuclear magnetic resonance spectroscopy (NMR), isothermal titration calorimetry (ITC), and microtiter plate assays. They found that the loss in affinity above pH 6.0 is mediated by the change in ionization state of a histidine residue that is not in the HA binding site. The change in charge state of this residue is relayed to HA-binding residues via a network involving a salt bridge and a hydrogen bond. A different histidine is responsible for the gain in TSG-6 affinity for HA between pH 3.5 and 6.0. This histidine influences ligand binding via its proximity to a loop that undergoes a conformational change on interaction with HA. This study provides new insight into the mechanisms by which the link module family proteins interact with HA in their wide range of biological functions.

FOOTNOTES

See referenced article, J. Biol. Chem. 2007, 282, 12976-12988

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