Structural basis for feedforward control in the PINK1/Parkin pathway
| Autor: | Kalle Gehring, Edward A. Fon, Véronique Sauvé, George Sung, Guennadi Kozlov, Rayan Fakih, Anshu Saran, Emma J. MacDougall |
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| Rok vydání: | 2022 |
| Předmět: |
biology
General Immunology and Microbiology Ubiquitin Chemistry Ubiquitin-Protein Ligases General Neuroscience PINK1 Mitochondrion Parkin General Biochemistry Genetics and Molecular Biology nervous system diseases Cell biology Ubiquitin ligase Ubiquitins Protein Domains biology.protein Phosphorylation Binding site Protein Kinases Molecular Biology |
| Zdroj: | The EMBO Journal. 41 |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.2021109460 |
| Popis: | PINK1 and parkin constitute a mitochondrial quality control system mutated in Parkinson’s disease. PINK1, a kinase, phosphorylates ubiquitin to recruit parkin, an E3 ubiquitin ligase, to mitochondria. PINK1 controls both parkin localization and activity through phosphorylation of both ubiquitin and the ubiquitin-like (Ubl) domain of parkin. Here, we observe that phospho-ubiquitin can bind to two distinct sites on parkin, a high affinity site on RING1 that controls parkin localization, and a low affinity site on RING0 that releases parkin autoinhibition. Surprisingly, NMR titrations and ubiquitin vinyl sulfone assays show that the RING0 site has higher affinity for phospho-ubiquitin than the phosphorylated Ubl. Parkin could be activated by micromolar concentrations of tetra-phospho-ubiquitin chains that mimic a mitochondrion bearing multiple phosphorylated ubiquitins. A chimeric form of parkin with the Ubl domain replaced by ubiquitin was readily activated by PINK1 phosphorylation. In all cases, mutation of the binding site on RING0 abolished parkin activation. The feedforward mechanism of parkin activation confers robustness and rapidity to the PINK1-parkin pathway and likely represents an intermediate step in its evolutionary development. |
| Databáze: | OpenAIRE |
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