6HUE

ParkinS65N

6HUE の概要

• エントリーDOI: 10.2210/pdb6hue/pdb
• 分子名称: E3 ubiquitin-protein ligase parkin, ZINC ION, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: e3 ligase, ligase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 92982.03

構造登録者

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. (登録日: 2018-10-07, 公開日: 2018-10-17, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.85 Å)