Clear Search sequence regions


  • adp (1)
  • amp pnp (1)
  • donor (1)
  • Gly (1)
  • help (1)
  • human (2)
  • kinetin (7)
  • nucleotides (4)
  • parkinson disease (3)
  • pediculus (1)
  • phosphate (1)
  • PINK1 (11)
  • protein kinases (2)
  • ubiquitin (5)
  • Sizes of these terms reflect their relevance to your search.

    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 Pediculus humanus corporis (Ph) 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 PhPINK1 or human (Hs) 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. HsPINK1 M318G can be used to conditionally uncouple PINK1 stabilization and activity on mitochondria.

    Citation

    Zhong Yan Gan, Sylvie Callegari, Thanh N Nguyen, Nicholas S Kirk, Andrew Leis, Michael Lazarou, Grant Dewson, David Komander. Interaction of PINK1 with nucleotides and kinetin. Science advances. 2024 Jan 19;10(3):eadj7408

    Expand section icon Mesh Tags

    Expand section icon Substances


    PMID: 38241364

    View Full Text