Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis

Abstract

The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N‐terminal ubiquitin‐like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin‐binding interface, provide a model for the phosphoubiquitin–parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin‐binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.

Cited by papers we hold 10

• The roles of E3 ubiquitin ligases in cancer progression and targeted therapy · 2023
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• Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis · 2021
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• Molecular mechanisms and physiological functions of mitophagy · 2021
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• Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly · 2021
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• Critical role of mitochondrial ubiquitination and the OPTN–ATG9A axis in mitophagy · 2020
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• PINK1/PARKIN signalling in neurodegeneration and neuroinflammation · 2020
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• Phosphorylation of Parkin at serine 65 is essential for its activation in vivo · 2018
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• PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy · 2018
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• The critical roles of mitophagy in cerebral ischemia · 2016
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• Ubiquitin modifications · 2016
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