Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site
| Autor: | Niv Papo, Evette S. Radisky, Yulia Shmidov, Shiran Lacham-Hartman, Ronit Bitton, David B. Lukatsky |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Protein Folding Dimer Cooperativity Biochemistry Physical Chemistry chemistry.chemical_compound Chemical Equilibrium Catalytic Domain Macromolecular Structure Analysis Amyloid precursor protein Trypsin Enzyme Inhibitors Receptor Materials chemistry.chemical_classification Multidisciplinary biology Monomers Proteases Ligand (biochemistry) Enzymes Chemistry Monomer Physical Sciences Medicine Research Article Protein Binding Protein Structure Science Materials Science Avidity Binding site Dimers Protein Interactions Molecular Biology Binding Sites Biology and Life Sciences Proteins Active site Polymer Chemistry Enzyme chemistry Oligomers Enzymology biology.protein Biophysics Serine Proteases Protein Multimerization |
| Zdroj: | PLoS ONE, Vol 16, Iss 11, p e0249616 (2021) PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0249616 |
| Popis: | Although myriad protein–protein interactions in nature use polyvalent binding, in which multiple ligands on one entity bind to multiple receptors on another, to date an affinity advantage of polyvalent binding has been demonstrated experimentally only in cases where the target receptor molecules are clustered prior to complex formation. Here, we demonstrate cooperativity in binding affinity (i.e., avidity) for a protein complex in which an engineered dimer of the amyloid precursor protein inhibitor (APPI), possessing two fully functional inhibitory loops, interacts with mesotrypsin, a soluble monomeric protein that does not self-associate or cluster spontaneously. We found that each inhibitory loop of the purified APPI homodimer was over three-fold more potent than the corresponding loop in the monovalent APPI inhibitor. This observation is consistent with a suggested mechanism whereby the two APPI loops in the homodimer simultaneously and reversibly bind two corresponding mesotrypsin monomers to mediate mesotrypsin dimerization. We propose a simple model for such dimerization that quantitatively explains the observed cooperativity in binding affinity. Binding cooperativity in this system reveals that the valency of ligands may affect avidity in protein–protein interactions including those of targets that are not surface-anchored and do not self-associate spontaneously. In this scenario, avidity may be explained by the enhanced concentration of ligand binding sites in proximity to the monomeric target, which may favor rebinding of the multiple ligand binding sites with the receptor molecules upon dissociation of the protein complex.Impact statementLacham-Hartman et al. demonstrate enhancement of binding affinity through avidity in a complex between a bivalent ligand and a soluble monomeric target with a single binding site. Avidity effects have previously been demonstrated only for clustered receptor molecules presenting multiple binding sites. Our model may explain how polyvalent ligands can agonize or antagonize biological interactions involving nonclustered target molecules that are crucial for intra- and extracellular structural, metabolic, signaling, and regulatory pathways. |
| Databáze: | OpenAIRE |
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