Avidity observed between a bivalent inhibitor and an enzyme monomer with a single active site.

Autor: Lacham-Hartman S; Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Shmidov Y; Deprtment of Chemical Engineering and the Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Radisky ES; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, United States of America., Bitton R; Deprtment of Chemical Engineering and the Ilse Katz Institute for Nanoscale Science & Technology, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Lukatsky DB; Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Papo N; Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and the National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Nov 30; Vol. 16 (11), pp. e0249616. Date of Electronic Publication: 2021 Nov 30 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0249616
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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