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The role of isoaspartate in fibrillation and its prevention by Protein-L-isoaspartyl methyltransferase
T. Chatterjee, G. Das, B.K. Chatterjee, J. Dhar, , P. Chakrabarti
Published in Elsevier B.V.
PMID: 31785325
Volume: 1864
Issue: 3
Background: Isomerization of aspartate to isoaspartate (isoAsp) on aging causes protein damage and malfunction. Protein-L-isoaspartyl methyltransferase (PIMT) performs a neuroprotective role by repairing such residues. A hexapeptide, Val-Tyr-Pro-(isoAsp)-His-Ala (VA6), a substrate of PIMT, is shown to form fibrils, while the normal Asp-containing peptide does not. Considering the role of PIMT against epileptic seizure, the combined effect of PIMT and two antiepileptic drugs (AEDs) (valproic acid and stiripentol) was investigated for anti-fibrillation activity. Methods: Structural/functional modulations due to the binding of AEDs to PIMT were investigated using biophysical techniques. Thioflavin T (ThT) fluorescence assay and microscopic methods were employed to study fibril formation by VA6. In vitro experiments with PC12 cells were carried out with PIMT/AEDs. Results: ThT assay indicated reduction of fibrillation of VA6 by PIMT. AEDs stabilize PIMT, bind close to the cofactor binding site, possibly exerting allosteric effect, increase the enzymatic activity, and anti-fibrillation efficacy. Furthermore, Aβ42, implicated in Alzheimer's disease, undergoes β-sheet to α-helix transition in presence of PIMT. Studies with PC12 derived neurons showed that PIMT and PIMT/AEDs exerted neuroprotective effect against anti-NGF induced neurotoxicity. This was further validated against neurotoxicity induced by Aβ42 in primary rat cortical neurons. Conclusions: The study provides a new perspective to the role isoAsp in protein fibrillation, PIMT in its prevention and AEDs in enhancing the activity of the enzyme. General significance: IsoAsp, with an additional C atom in the main-chain of polypeptide chain, may make it more susceptible to fibrillation. PIMT alone, or in association with AEDs prevents this. © 2019 Elsevier B.V.
About the journal
JournalData powered by TypesetBiochimica et Biophysica Acta - General Subjects
PublisherData powered by TypesetElsevier B.V.