Abstract
Structural changes in human serum albumin (HSA) induced by the pollutants 1-naphthol, 2-naphthol and 8-quinolinol were analyzed by circular dichroism, fluorescence spectroscopy and dynamic light scattering. The alteration in protein conformational stability was determined by helical content induction (from 55 to 75%) upon protein-pollutant interactions. Domain plasticity is responsible for the temperature-mediated unfolding of HSA. These findings were compared to HSA-hydrolase activity. We found that though HSA is a monomeric protein, it shows heterotropic allostericity for β-lactamase activity in the presence of pollutants, which act as K- and V-type non-essential activators. Pollutants cause conformational changes and catalytic modifications of the protein (increase in β-lactamase activity from 100 to 200%). HSA-pollutant interactions mediate other protein-ligand interactions, such as HSA-nitrocefin. Therefore, this protein can exist in different conformations with different catalytic properties depending on activator binding. This is the first report to demonstrate the catalytic allostericity of HSA through a mechanistic approach. We also show a correlation with non-microbial drug resistance as HSA is capable of self-hydrolysis of β-lactam drugs, which is further potentiated by pollutants due to conformational changes in HSA.
Highlights
Human serum albumin (HSA) is the most abundant multifunctional single chain protein in blood plasma
Factors that drive helix formation must originate in the backbone as the helix is an energetically favored structure [33]. These factors may be intrinsic to protein sequence in physiological conditions or they may be induced by external factors
It may be possible that amino acids having the propensity of helix non-formation in water are somehow changed to helix forming residues when this amino acid comes in the vicinity of pollutant molecules
Summary
Human serum albumin (HSA) is the most abundant multifunctional single chain protein in blood plasma. HSA plays important physiological and pharmacokinetical roles by binding and transporting exo- and endo-genous compounds [1,2]. It possesses some enolase, esterase and hydrolase activities [3]. As a consequence of the alteration in the nature of the local environment surrounding Cys-34, the long chain of fatty acid regulates the radical-trapping antioxidant activity [8]. These ligand-dependent changes in protein conformations are specific to the type of ligands and more precisely to their capacity to accumulate in the binding pockets. The ligand-induced structural changes in HSA are suggested to mediate its role in receptormediated cellular interaction as well as solute transport in physiological conditions
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