In silico analysis of alpha-synuclein protein variants and posttranslational modifications related to Parkinson's disease.

Autor: da Silva ANR; Bioinformatics and Computational Biology Laboratory, Department of Genetics and Molecular Biology, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil., Pereira GRC; Bioinformatics and Computational Biology Laboratory, Department of Genetics and Molecular Biology, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil., Bonet LFS; Bioinformatics and Computational Biology Laboratory, Department of Genetics and Molecular Biology, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil., Outeiro TF; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany.; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.; Max Planck Institute for Experimental Medicine, Göttingen, Germany., De Mesquita JF; Bioinformatics and Computational Biology Laboratory, Department of Genetics and Molecular Biology, Federal University of the State of Rio de Janeiro (UNIRIO), Rio de Janeiro, Rio de Janeiro, Brazil.
Jazyk: angličtina
Zdroj: Journal of cellular biochemistry [J Cell Biochem] 2024 Mar; Vol. 125 (3), pp. e30523. Date of Electronic Publication: 2024 Jan 18.
DOI: 10.1002/jcb.30523
Abstrakt: Parkinson's disease (PD) is among the most prevalent neurodegenerative disorders, affecting over 10 million people worldwide. The protein encoded by the SNCA gene, alpha-synuclein (ASYN), is the major component of Lewy body (LB) aggregates, a histopathological hallmark of PD. Mutations and posttranslational modifications (PTMs) in ASYN are known to influence protein aggregation and LB formation, possibly playing a crucial role in PD pathogenesis. In this work, we applied computational methods to characterize the effects of missense mutations and PTMs on the structure and function of ASYN. Missense mutations in ASYN were compiled from the literature/databases and underwent a comprehensive predictive analysis. Phosphorylation and SUMOylation sites of ASYN were retrieved from databases and predicted by algorithms. ConSurf was used to estimate the evolutionary conservation of ASYN amino acids. Molecular dynamics (MD) simulations of ASYN wild-type and variants A30G, A30P, A53T, and G51D were performed using the GROMACS package. Seventy-seven missense mutations in ASYN were compiled. Although most mutations were not predicted to affect ASYN stability, aggregation propensity, amyloid formation, and chaperone binding, the analyzed mutations received relatively high rates of deleterious predictions and predominantly occurred at evolutionarily conserved sites within the protein. Moreover, our predictive analyses suggested that the following mutations may be possibly harmful to ASYN and, consequently, potential targets for future investigation: K6N, T22I, K34E, G36R, G36S, V37F, L38P, G41D, and K102E. The MD analyses pointed to remarkable flexibility and essential dynamics alterations at nearly all domains of the studied variants, which could lead to impaired contact between NAC and the C-terminal domain triggering protein aggregation. These alterations may have functional implications for ASYN and provide important insight into the molecular mechanism of PD, supporting the design of future biomedical research and improvements in existing therapies for the disease.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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