8UYF

Structure of nucleotide-free Pediculus humanus (Ph) PINK1 dimer

Summary for 8UYF

• Entry DOI: 10.2210/pdb8uyf/pdb
• EMDB information: 42804 42806 42807
• Descriptor: Serine/threonine-protein kinase Pink1, mitochondrial (1 entity in total)
• Functional Keywords: pink1, kinase, mitophagy, parkinson's disease, ubiquitin, phosphorylation, phospho-ubiquitin, transferase
• Biological source: Pediculus humanus corporis (human body louse)
• Total number of polymer chains: 2
• Total formula weight: 106107.20

Authors

Gan, Z.Y.,Kirk, N.S.,Leis, A.,Komander, D. (deposition date: 2023-11-13, release date: 2024-01-31, Last modification date: 2024-10-09)

Primary citation

Gan, Z.Y.,Callegari, S.,Nguyen, T.N.,Kirk, N.S.,Leis, A.,Lazarou, M.,Dewson, G.,Komander, D.
Interaction of PINK1 with nucleotides and kinetin.
Sci Adv, 10:eadj7408-eadj7408, 2024

PubMed Abstract: 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.

PubMed: 38241364
DOI: 10.1126/sciadv.adj7408

Experimental method

ELECTRON MICROSCOPY (2.75 Å)