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-Structure paper
タイトル | Interaction of PINK1 with nucleotides and kinetin. |
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ジャーナル・号・ページ | Sci Adv, Vol. 10, Issue 3, Page eadj7408, Year 2024 |
掲載日 | 2024年1月19日 |
著者 | Zhong Yan Gan / Sylvie Callegari / Thanh N Nguyen / Nicholas S Kirk / Andrew Leis / Michael Lazarou / Grant Dewson / David Komander / |
PubMed 要旨 | The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin ...The ubiquitin kinase PINK1 accumulates on damaged mitochondria to trigger mitophagy, and PINK1 loss-of-function mutations cause early onset Parkinson's disease. Nucleotide analogs such as kinetin triphosphate (KTP) were reported to enhance PINK1 activity and may represent a therapeutic strategy for the treatment of Parkinson's disease. Here, we investigate the interaction of PINK1 with nucleotides, including KTP. We establish a cryo-EM platform exploiting the dodecamer assembly of () PINK1 and determine PINK1 structures bound to AMP-PNP and ADP, revealing conformational changes in the kinase N-lobe that help establish PINK1's ubiquitin binding site. Notably, we find that KTP is unable to bind PINK1 or human () PINK1 due to a steric clash with the kinase "gatekeeper" methionine residue, and mutation to Ala or Gly is required for PINK1 to bind and use KTP as a phosphate donor in ubiquitin phosphorylation and mitophagy. PINK1 M318G can be used to conditionally uncouple PINK1 stabilization and activity on mitochondria. |
リンク | Sci Adv / PubMed:38241364 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.75 - 3.13 Å |
構造データ | EMDB-42804, PDB-8uyf: EMDB-42806, PDB-8uyh: EMDB-42807, PDB-8uyi: |
化合物 | ChemComp-ANP: ChemComp-MG: ChemComp-ADP: |
由来 |
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キーワード | TRANSFERASE / PINK1 / Kinase / Mitophagy / Parkinson's Disease / Ubiquitin / Phosphorylation / Phospho-ubiquitin |