Mechanism of human PINK1 activation at the TOM complex in a reconstituted system-Reference-Cited by-同舟云学术

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

Published:2024-06-07 Issue:23 Volume:10 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Raimi Olawale G.¹^ORCID,Ojha Hina¹,Ehses Kenneth²³^ORCID,Dederer Verena⁴⁵⁶^ORCID,Lange Sven M.¹^ORCID,Rivera Cristian Polo¹^ORCID,Deegan Tom D.¹⁷,Chen Yinchen¹,Wightman Melanie¹,Toth Rachel¹^ORCID,Labib Karim P. M.¹^ORCID,Mathea Sebastian⁴⁵⁶^ORCID,Ranson Neil⁸^ORCID,Fernández-Busnadiego Rubén²³⁴⁹^ORCID,Muqit Miratul M. K.¹⁴^ORCID

Affiliation:

1. MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

2. Institute of Neuropathology, University Medical Center Göttingen, 37099 Göttingen, Germany.

3. Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany.

4. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.

5. Institute of Pharmaceutical Chemistry, Goethe-Universität, 60438 Frankfurt, Germany.

6. Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Goethe-Universität, 60438 Frankfurt, Germany.

7. MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.

8. Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.

9. Faculty of Physics, University of Göttingen, Friedrich-Hund-Platz 1, 37077 Göttingen, Germany.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/sciadv.adn7191

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