Structural basis for feedforward control in the PINK1/Parkin pathway

Abstract: 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 observed 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, ubiquitin vinyl sulfone assays, ITC, and NMR titrations showed that the RING0 site has higher affinity for phospho‐ubiquitin than phosphorylated Ubl in trans. We observed parkin activation by micromolar concentrations of tetra‐phospho‐ubiquitin chains that mimic mitochondria 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.

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Structural basis for feedforward control in the PINK1/Parkin pathway ; day:02 ; month:05 ; year:2022 ; extent:13 ; The EMBO journal / European Molecular Biology Organization ; (02.05.2022) (gesamt 13)

Contributors, Places and Time

• Creator: Sauvé, Véronique ; Sung, George ; MacDougall, Emma J. ; Kozlov, Guennadi ; Saran, Anshu ; Fakih, Rayan ; Fon, Edward A. ; Gehring, Kalle

Further information

• DOI: 10.15252/embj.2021109460
• URN: urn:nbn:de:101:1-2022050215173048547176
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 15.08.2025, 7:31 AM CEST