1. CD44 receptor unfolding enhances binding by freeing basic amino acids to contact carbohydrate ligand.
- Author
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Favreau AJ, Faller CE, and Guvench O
- Subjects
- Allosteric Regulation, Amino Acid Substitution, Humans, Hyaluronan Receptors genetics, Ligands, Mutation, Protein Binding, Protein Stability, Protein Structure, Tertiary, Thermodynamics, Amino Acids, Basic, Hyaluronan Receptors chemistry, Hyaluronan Receptors metabolism, Hyaluronic Acid metabolism, Molecular Dynamics Simulation, Protein Unfolding
- Abstract
The extracellular carbohydrate-binding domain of the Type I transmembrane receptor CD44 is known to undergo affinity switching, where change in conformation leads to enhanced binding of its carbohydrate ligand hyaluronan. Separate x-ray crystallographic and NMR experiments have led to competing explanations, with the former supporting minor conformational changes at the binding site and the latter a major order-to-disorder unfolding transition distant from the binding site. Here, all-atom explicit-solvent molecular dynamics studies employing adaptive biasing force sampling revealed a substantial favorable free-energy change associated with contact formation between the Arg(41) side chain and hyaluronan at the binding site, independent of whether the distant site was ordered or disordered. Analogous computational experiments on Arg(41)Ala mutants showed loss of this favorable free-energy change, consistent with existing experimental data. More provocatively, the simulation data revealed the molecular mechanism by which the order-to-disorder transition enhances hyaluronan binding: in the disordered state, a number of basic residues gain sufficient conformational freedom-lacking in the ordered state-to spontaneously form side-chain contacts with hyaluronan. Mutation of these residues to Ala had been known to decrease binding affinity, but there had previously been no structural explanation, given their lack of proximity to the carbohydrate-binding site in existing structures of the complex., (Copyright © 2013 Biophysical Society. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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