دورية أكاديمية
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Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.

التفاصيل البيبلوغرافية
العنوان: Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
المؤلفون: Raimi OG; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Ojha H; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Ehses K; Institute of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany., Dederer V; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.; Institute of Pharmaceutical Chemistry, Goethe-Universität, 60438 Frankfurt, Germany.; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-Universität, 60438 Frankfurt, Germany., Lange SM; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Rivera CP; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Deegan TD; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.; MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK., Chen Y; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Wightman M; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Toth R; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Labib KPM; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK., Mathea S; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.; Institute of Pharmaceutical Chemistry, Goethe-Universität, 60438 Frankfurt, Germany.; Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-Universität, 60438 Frankfurt, Germany., Ranson N; Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK., Fernández-Busnadiego R; Institute of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.; Faculty of Physics, University of Göttingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany., Muqit MMK; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
المصدر: Science advances [Sci Adv] 2024 Jun 07; Vol. 10 (23), pp. eadn7191. Date of Electronic Publication: 2024 Jun 07.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]-
مواضيع طبية MeSH: Protein Kinases*/metabolism , Protein Kinases*/genetics , Mitochondrial Precursor Protein Import Complex Proteins*/metabolism , Mitochondrial Membrane Transport Proteins*/metabolism , Mitochondrial Membrane Transport Proteins*/genetics , Saccharomyces cerevisiae*/metabolism , Saccharomyces cerevisiae*/genetics, Humans ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Mitochondria/metabolism ; Protein Binding ; Enzyme Activation ; Models, Molecular ; Protein Subunits/metabolism ; Protein Subunits/genetics
مستخلص: Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.
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المشرفين على المادة: EC 2.7.11.1 (PTEN-induced putative kinase)
EC 2.7.- (Protein Kinases)
0 (Mitochondrial Precursor Protein Import Complex Proteins)
0 (Mitochondrial Membrane Transport Proteins)
0 (Saccharomyces cerevisiae Proteins)
0 (TOMM20 protein, human)
0 (Protein Subunits)
تواريخ الأحداث: Date Created: 20240607 Date Completed: 20240607 Latest Revision: 20240609
رمز التحديث: 20240609
مُعرف محوري في PubMed: PMC11160474
DOI: 10.1126/sciadv.adn7191
PMID: 38848361
قاعدة البيانات: MEDLINE
الوصف
تدمد:2375-2548
DOI:10.1126/sciadv.adn7191