EMD-42804

Single-particle
2.75 Å
EMD-42804 Deposition: 13/11/2023
Map released: 31/01/2024
Last modified: 09/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links

EMD-42804

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

EMD-42804

Single-particle
2.75 Å
EMD-42804 Deposition: 13/11/2023
Map released: 31/01/2024
Last modified: 09/10/2024
Overview 3D View Sample Experiment Validation Volume Browser Additional data Links
Sample Organism: Pediculus humanus corporis
Sample: Nucleotide-free Pediculus humanus (Ph) PINK1 dodecamer
Fitted models: 8uyf (Avg. Q-score: 0.56)

Deposition Authors: Gan ZY , Kirk NS , Leis A , Komander D
Interaction of PINK1 with nucleotides and kinetin.
Gan ZY , Callegari S , Nguyen TN , Kirk NS , Leis A , Lazarou M , Dewson G , Komander D
(2024) Sci Adv , 10 , eadj7408 - eadj7408
PUBMED: 38241364
DOI: doi:10.1126/sciadv.adj7408
ISSN: 2375-2548
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 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.