title: The complex interplay between ligand binding and conformational structure of the folate binding protein (folate receptor): Biological perspectives.
abstract: This review analyzes how interplay between folate binding and changes in folate binding protein (FBP) conformation/self-association affects the biological function of FBP. Concentration-dependent, reversible self-association of hydrophobic apo-FBP at pI=7.4 is associated with decreased affinity for folate, probably due to shielding of binding sites between interacting hydrophobic patches. Titration with folate removes apo-monomers, favoring dissociation of self-associated apo-FBP into apo-monomers. Folate anchors to FBP through a network of hydrogen bonds and hydrophobic interactions, and the binding induces a conformational change with formation of hydrophilic and stable holo-FBP. Holo-FBP exhibits a ligand-mediated concentration-dependent self-association into multimers of great thermal and chemical stability due to strong intermolecular forces. Both ligand and FBP are thus protected against biological/physicochemical decomposition. In biological fluids with low FBP concentrations, e.g., saliva, semen and plasma, hydrophobic apo-monomers and hydrophilic holo-monomers associate into stable asymmetrical complexes with aberrant binding kinetics unless detergents, e.g., cholesterol or phospholipids are present.
authors.affiliation: Department of Clinical Biochemistry, Nordsjællands Hospital - Hillerød, University Hospital Copenhagen, Dyrehavevej 29, DK-3400 Hillerød, Denmark. Electronic address: Janmfholm@gmail.com.
authors.forename: Jan
authors.initials: J
authors.lastname: Holm
authors.affiliation: Faculty of Science, Department of Food Science, Spectroscopy and Chemometrics, University of Copenhagen, Rolighedsvej 26, DK-1958 Frederiksberg, Denmark.
authors.forename: Susanne W
authors.initials: SW
authors.lastname: Bruun
authors.affiliation: Department of Clinical Biochemistry, Nordsjællands Hospital - Hillerød, University Hospital Copenhagen, Dyrehavevej 29, DK-3400 Hillerød, Denmark. Electronic address: Steen.Ingemann.Hansen@Regionh.dk.
authors.forename: Steen I
authors.initials: SI
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001059:Apoproteins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D058973:Folate Receptors, GPI-Anchored / Q000737:chemistry* / Q000378:metabolism; D005492:Folic Acid / Q000737:chemistry* / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012463:Saliva / Q000737:chemistry / Q000378:metabolism; D012661:Semen / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001059:Apoproteins; D058973:Folate Receptors, GPI-Anchored; D008024:Ligands; D005492:Folic Acid
keywords: Asymmetrical (apo–holo) self-association; Binding-induced structural changes; Folate binding protein (folate receptor); High-affinity folate binding; Ligand-mediated self-association; Stable holo-multimers