Chaperone-like effect of ceftriaxone on HEWL aggregation: A spectroscopic and computational study

DOI: 10.1016/j.bbagen.2018.02.014

Authors: Paolo Ruzza (Institute of Biomolecular Chemistry of CNR) , Rosa Maria Vitale (Institute of Biomolecular Chemistry of CNR) , Rohanah Hussain (Diamond Light Source) , Alessia Montini (Institute of Biomolecular Chemistry of CNR) , Claudia Honisch (Institute of Biomolecular Chemistry of CNR) , Alice Pozzebon (Institute of Biomolecular Chemistry of CNR) , Charlotte S. Hughes (Diamond Light Source) , Barbara Biondi (Institute of Biomolecular Chemistry of CNR) , Pietro Amodeo (Institute of Biomolecular Chemistry of CNR) , Gianpietro Sechi (University of Sassari) , Giuliano Siligardi (Diamond Light Source)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochimica Et Biophysica Acta (bba) - General Subjects

State: Published (Approved)
Published: March 2018
Diamond Proposal Number(s): 8034

Abstract: Background: Lysozyme is a widely distributed enzyme present in a variety of tissue and body fluids. Human and hen egg white lysozyme are used as validated model to study protein folding and stability and to understand protein misfolding and aggregation. We recently found that ceftriaxone, a β-lactam antibiotic able to overcome the blood-brain barrier, successfully eliminated the cellular toxic effects of misfolded proteins as Glial Fibrillary Acidic Protein and α-synuclein. To further understand the anti-amyloidogenic properties of ceftriaxone, we studied its activity towards lysozyme aggregation with the aim to investigate a possible chaperone-like activity of this molecule. Methods: Here we present the results obtained from fluorescence and synchrotron radiation circular dichroism spectroscopies and from molecular docking and molecular dynamics about the lysozyme-ceftriaxone interaction at neutral and acidic pH values. Results: We found that ceftriaxone exhibits comparable affinity constants to lysozyme in both experimental pH conditions and that its addition enhanced lysozyme stability reducing its aggregation propensity in acidic conditions. Computational methods allowed the identification of the putative binding site of ceftriaxone, thus rationalizing the spectroscopic results. Conclusions: Spectroscopy data and molecular dynamics indicated a protective effect of ceftriaxone on pathological aggregation phenomena suggesting a chaperone-like effect of this molecule on protein folding. General significance: These results, in addition to our previous studies on α-synuclein and GFAP, confirm the property of ceftriaxone to inhibit the pathological protein aggregation of lysozyme also by a chaperone-like mechanism, extending the potential therapeutic application of this molecule to some forms of human hereditary systemic amyloidosis.

Journal Keywords: Ceftriaxone; Lysozyme; Misfolding diseases; Synchrotron radiation circular dichroism spectroscopy; Molecular docking; Molecular dynamics

Subject Areas: Biology and Bio-materials, Medicine


Instruments: B23-Circular Dichroism

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