CD44 Binding to Hyaluronic Acid Is Redox Regulated by a Labile Disulfide Bond in the Hyaluronic Acid Binding Site

CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity....

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Bibliographic Details
Published in:PloS one 2015-09, Vol.10 (9), p.e0138137-e0138137
Main Authors: Kellett-Clarke, Helena, Stegmann, Monika, Barclay, A Neil, Metcalfe, Clive
Format: Article
Language:English
Subjects:
Acids
Allosteric properties
Animals
Binding Sites
Blood clots
Blood platelets
Bonds (Securities)
Cancer
CD44 antigen
Cell Adhesion
Cell Line
Cell surface
Chemical bonds
Chemical properties
CHO Cells
Cricetulus
Crystal structure
Crystallography, X-Ray
Dendritic cells
Disulfide bonds
Enzymes
Extracellular matrix
Fc receptors
Humans
Hyaluronan Receptors - genetics
Hyaluronan Receptors - metabolism
Hyaluronan Receptors - ultrastructure
Hyaluronic acid
Hyaluronic Acid - metabolism
Hydrothermal crystal growth
Immune response
Leukocytes
Lymphocytes
Mass spectrometry
Mice
Oxidation-Reduction
Pathology
Protein Binding
Proteins
Receptors, Fc - genetics
Receptors, Fc - metabolism
Recombinant Fusion Proteins - metabolism
Reducing agents
Rheumatoid arthritis
Scientific imaging
T cell receptors
Transfection
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Summary:CD44 is the primary leukocyte cell surface receptor for hyaluronic acid (HA), a component of the extracellular matrix. Enzymatic post translational cleavage of labile disulfide bonds is a mechanism by which proteins are structurally regulated by imparting an allosteric change and altering activity. We have identified one such disulfide bond in CD44 formed by Cys77 and Cys97 that stabilises the HA binding groove. This bond is labile on the surface of leukocytes treated with chemical and enzymatic reducing agents. Analysis of CD44 crystal structures reveal the disulfide bond to be solvent accessible and in the-LH hook configuration characteristic of labile disulfide bonds. Kinetic trapping and binding experiments on CD44-Fc chimeric proteins show the bond is preferentially reduced over the other disulfide bonds in CD44 and reduction inhibits the CD44-HA interaction. Furthermore cells transfected with CD44 no longer adhere to HA coated surfaces after pre-treatment with reducing agents. The implications of CD44 redox regulation are discussed in the context of immune function, disease and therapeutic strategies.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0138137