Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1)
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 part...
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doaj-7e2ec4eee7964fa3bd2acef156c3f96c2021-01-02T05:08:32ZengElsevierComputational and Structural Biotechnology Journal2001-03702020-01-011810321042Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1)Kirsten Jenkins0Teodora Mateeva1István Szabó2Andre Melnik3Paola Picotti4Attila Csikász-Nagy5Edina Rosta6Randall Division of Cell and Molecular Biophysics, Institute for Mathematical and Molecular Biomedicine, King’s College London, London SE1 1UL, UKDepartment of Chemistry, King’s College London, London SE1 1DB, UKDepartment of Chemistry, King’s College London, London SE1 1DB, UKInstitute of Biochemistry, Department of Biology, ETH Zurich, CH-8093 Zurich, SwitzerlandInstitute of Biochemistry, Department of Biology, ETH Zurich, CH-8093 Zurich, SwitzerlandRandall Division of Cell and Molecular Biophysics, Institute for Mathematical and Molecular Biomedicine, King’s College London, London SE1 1UL, UK; Faculty of Information Technology and Bionics, Pázmány Péter Catholic University, 1083 Budapest, HungaryDepartment of Chemistry, King’s College London, London SE1 1DB, UK; Corresponding author.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 α-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.http://www.sciencedirect.com/science/article/pii/S2001037020300428Data integrationMolecular dynamics (MD)Neurodegenerative diseasesParkinson’s disease (PD)Synaptojanin-1α-Synuclein |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kirsten Jenkins Teodora Mateeva István Szabó Andre Melnik Paola Picotti Attila Csikász-Nagy Edina Rosta |
spellingShingle |
Kirsten Jenkins Teodora Mateeva István Szabó Andre Melnik Paola Picotti Attila Csikász-Nagy Edina Rosta Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1) Computational and Structural Biotechnology Journal Data integration Molecular dynamics (MD) Neurodegenerative diseases Parkinson’s disease (PD) Synaptojanin-1 α-Synuclein |
author_facet |
Kirsten Jenkins Teodora Mateeva István Szabó Andre Melnik Paola Picotti Attila Csikász-Nagy Edina Rosta |
author_sort |
Kirsten Jenkins |
title |
Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1) |
title_short |
Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1) |
title_full |
Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1) |
title_fullStr |
Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1) |
title_full_unstemmed |
Combining data integration and molecular dynamics for target identification in α-Synuclein-aggregating neurodegenerative diseases: Structural insights on Synaptojanin-1 (Synj1) |
title_sort |
combining data integration and molecular dynamics for target identification in α-synuclein-aggregating neurodegenerative diseases: structural insights on synaptojanin-1 (synj1) |
publisher |
Elsevier |
series |
Computational and Structural Biotechnology Journal |
issn |
2001-0370 |
publishDate |
2020-01-01 |
description |
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 α-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. |
topic |
Data integration Molecular dynamics (MD) Neurodegenerative diseases Parkinson’s disease (PD) Synaptojanin-1 α-Synuclein |
url |
http://www.sciencedirect.com/science/article/pii/S2001037020300428 |
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