Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1)
| Autor: | Paola Picotti, Kirsten Jenkins, István Szabó, Andre Melnik, Edina Rosta, Teodora Mateeva, Attila Csikász-Nagy |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Parkinson's disease (PD)
lcsh:Biotechnology Biophysics Computational biology Disease Protein aggregation Biochemistry Dephosphorylation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Synaptojanin-1 Structural Biology lcsh:TP248.13-248.65 Data integration Molecular dynamics (MD) Neurodegenerative diseases Parkinson’s disease (PD) a-Synuclein Genetics medicine Phosphatidylinositol Amyotrophic lateral sclerosis 030304 developmental biology α-Synuclein 0303 health sciences biology Neurodegeneration Active site medicine.disease 3. Good health Computer Science Applications chemistry 030220 oncology & carcinogenesis biology.protein Biotechnology Research Article |
| Zdroj: | Computational and Structural Biotechnology Journal, Vol 18, Iss, Pp 1032-1042 (2020) Mateeva, T, Rosta, E, Csikasz-Nagy, A & Jenkins, K 2020, ' Combining data integration and molecular dynamics for target identification in α-synuclein-aggregating neurodegenerative diseases : Structural insights on Synaptojanin-1 (Synj1) ', Journal of Computational and Structural Biotechnology, vol. 18, pp. 1032-1042 . https://doi.org/10.1016/j.csbj.2020.04.010 Computational and Structural Biotechnology Journal Computational and Structural Biotechnology Journal, 18 |
| ISSN: | 2001-0370 |
| Popis: | Parkinson's disease (PD), Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases hallmarked by the formation of toxic protein aggregates. However, targeting these aggregates therapeutically have thus far shown no success. The treatment of AD has remained particularly problematic since no new drugs have been approved in the last 15 years. Therefore, novel therapeutic targets need to be identified and explored. Here, through the integration of genomic and proteomic data, a set of proteins with strong links to alpha-synuclein-aggregating neurodegenerative diseases was identified. We propose 17 protein targets that are likely implicated in neurodegeneration and could serve as potential targets. The human phosphatidylinositol 5-phosphatase synaptojanin-1, which has already been independently confirmed to be implicated in Parkinson's and Alzheimer's disease, was among those identified. Despite its involvement in PD and AD, structural aspects are currently missing at the molecular level. We present the first atomistic model of the 5-phosphatase domain of synaptojanin-1 and its binding to its substrate phosphatidylinositol 4,5-bisphosphate (PIP2). We determine structural information on the active site including membrane-embedded molecular dynamics simulations. Deficiency of charge within the active site of the protein is observed, which suggests that a second divalent cation is required to complete dephosphorylation of the substrate. The findings in this work shed light on the protein's binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and give additional insight for future targeting of the protein active site, which might be of interest in neurodegenerative diseases where synaptojanin-1 is overexpressed. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. ISSN:2001-0370 |
| Databáze: | OpenAIRE |
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