Catechol-induced covalent modifications modulate the aggregation tendency of α-synuclein: An in-solution and in-silico study.
DOPAC‐induced covalent modification
amyloid inhibition
catechol
molecular dynamics simulation
native‐mass spectrometry
α‐Synuclein
Journal
BioFactors (Oxford, England)
ISSN: 1872-8081
Titre abrégé: Biofactors
Pays: Netherlands
ID NLM: 8807441
Informations de publication
Date de publication:
27 May 2024
27 May 2024
Historique:
received:
15
03
2024
accepted:
14
05
2024
medline:
27
5
2024
pubmed:
27
5
2024
entrez:
27
5
2024
Statut:
aheadofprint
Résumé
Parkinson's disease (PD) stands as a challenging neurodegenerative condition characterized by the emergence of Lewy Bodies (LBs), intracellular inclusions within dopaminergic neurons. These LBs harbor various proteins, prominently including α-Synuclein (Syn) aggregates, implicated in disease pathology. A promising avenue in PD treatment involves targeting Syn aggregation. Recent findings from our research have shown that 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylethanol (DOPET) possess the ability to impede the formation of Syn fibrils by disrupting the aggregation process. Notably, these compounds primarily engage in noncovalent interactions with the protein, leading to the formation of off-pathway oligomers that deter fibril growth. Through proteolysis studies and mass spectrometry (MS) analysis, we have identified potential covalent modifications of Syn in the presence of DOPAC, although the exact site remains elusive. Employing molecular dynamics simulations, we delved into how DOPAC-induced covalent alterations might affect the mechanism of Syn aggregation. Our findings indicate that the addition of a covalent adduct on certain residues enhances fibril flexibility without compromising its secondary structure stability. Furthermore, in the monomeric state, the modified residue fosters novel bonding interactions, thereby influencing long-range interactions between the N- and C-termini of the protein.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Progetti di Ateneo 2022 BIRD222840
ID : C93C22008380001
Organisme : PRIN 2022TWRXAW
ID : 2022TWRXAW
Informations de copyright
© 2024 International Union of Biochemistry and Molecular Biology.
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