EMD-42804
Structure of nucleotide-free Pediculus humanus (Ph) PINK1 dimer
EMD-42804
Single-particle2.75 Å

Map released: 31/01/2024
Last modified: 09/10/2024
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
Sample: Nucleotide-free Pediculus humanus (Ph) PINK1 dodecamer
Fitted models: 8uyf (Avg. Q-score: 0.56)
Deposition Authors: Gan ZY




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








(2024) Sci Adv , 10 , eadj7408 - eadj7408
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.
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.