Abstract
Fibrillation of peptides and proteins is implicated in various neurodegenerative diseases and is a global concern. Aging leads to the formation of abnormal isoaspartate (isoAsp) residues from isomerization of normal aspartates in proteins, triggering fibril formation that leads to neurodegenerative diseases. Protein L-isoaspartyl methyltransferase (PIMT) is a repair enzyme which recognizes and converts altered isoAsp residues back to normal aspartate. Here we report the effect of gold nanoparticles (AuNPs) of different sizes on the structure and function of PIMT. Spherical AuNPs, viz. AuNS5, AuNS50 and AuNS100 (the number indicating the diameter in nm) stabilize PIMT, with AuNS100 exhibiting the best efficacy, as evident from various biophysical experiments. Isothermal titration calorimetry (ITC) revealed endothermic, but entropy driven mode of binding of PIMT with all the three AuNSs. Methyltransferase activity assay showed enhanced activity of PIMT in presence of all AuNSs, the maximum being with AuNS100. The efficacy of PIMT in presence of AuNS100 was further demonstrated by the reduction of fibrillation of Aβ42, the peptide that is implicated in Alzheimer’s disease. The enhancement of anti-fibrillation activity of PIMT with AuNS100 was confirmed from cell survival assay with PC12 derived neuronal cells against Aβ42 induced neurotoxicity.
Highlights
Fibrillation of peptides and proteins is implicated in various neurodegenerative diseases and is a global concern
Surface Plasmon Resonance (SPR) bands which appear due to oscillation of conduction band electrons
We had shown that the enzyme Protein L-isoaspartyl methyltransferase (PIMT) can reduce the fibril formation in an isoAsp-containing peptide and this can be of general significance in all biologically relevant proteins that contain natural Asp or Asn residues that can get converted to isoAsp on a geing[10], Aβ42 being one such molecule
Summary
Fibrillation of peptides and proteins is implicated in various neurodegenerative diseases and is a global concern. Recent years have witnessed the use of AuNPs as promising therapeutic agents against fibrillation of peptides and proteins that are implicated in various neurodegenerative diseases[17,18,19]. In this context, considering the neuroprotective role of PIMT, we wanted to explore the role of spherical AuNPs of different sizes (AuNS5, AuNS50 and AuNS100, the number indicating the diameter of the nanospheres, AuNSs, in nm) in affecting the structure and function (notably the anti-fibrillation activity) of PIMT. To the best of our knowledge the structural/ functional modification of this ubiquitous repair enzyme PIMT by AuNPs has not been reported in literature till date and is likely to have bearing on the therapeutic application against various neurodegenerative diseases
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