6HUE

ParkinS65N

Summary for 6HUE

• Entry DOI: 10.2210/pdb6hue/pdb
• Descriptor: E3 ubiquitin-protein ligase parkin, ZINC ION, SULFATE ION, ... (6 entities in total)
• Functional Keywords: e3 ligase, ligase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 92982.03

Authors

McWilliams, T.G.,Barini, E.,Pohjolan-Pirhonen, R.,Brooks, S.P.,Singh, F.,Burel, S.,Balk, K.,Kumar, A.,Montava-Garriga, L.,Prescott, A.R.,Hassoun, S.M.,Mouton-Liger, F.,Ball, G.,Hills, R.,Knebel, A.,Ulusoy, A.,Di Monte, D.A.,Tamjar, J.,Antico, O.,Fears, K.,Smith, L.,Brambilla, R.,Palin, E.,Valori, M.,Eerola-Rautio, J.,Tienari, P.,Corti, O.,Dunnett, S.B.,Ganley, I.G.,Suomalainen, A.,Muqit, M.M.K. (deposition date: 2018-10-07, release date: 2018-10-17, Last modification date: 2024-01-24)

Primary citation

McWilliams, T.G.,Barini, E.,Pohjolan-Pirhonen, R.,Brooks, S.P.,Singh, F.,Burel, S.,Balk, K.,Kumar, A.,Montava-Garriga, L.,Prescott, A.R.,Hassoun, S.M.,Mouton-Liger, F.,Ball, G.,Hills, R.,Knebel, A.,Ulusoy, A.,Di Monte, D.A.,Tamjar, J.,Antico, O.,Fears, K.,Smith, L.,Brambilla, R.,Palin, E.,Valori, M.,Eerola-Rautio, J.,Tienari, P.,Corti, O.,Dunnett, S.B.,Ganley, I.G.,Suomalainen, A.,Muqit, M.M.K.
Phosphorylation of Parkin at serine 65 is essential for its activation in vivo .
Open Biology, 8:-, 2018

PubMed Abstract: Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in mammals remains unknown. To address this, we generated a Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in neurons. Phenotypically, mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN () p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the Parkin mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.

PubMed: 30404819
DOI: 10.1098/rsob.180108

Experimental method

X-RAY DIFFRACTION (2.85 Å)