AI Article Synopsis
- The study focuses on the role of the ubiquitin kinase PINK1 in promoting mitophagy, particularly its connection to early-onset Parkinson's disease when mutated.
- Researchers investigated how PINK1 interacts with various nucleotides, notably finding that the nucleotide analog kinetin triphosphate (KTP) does not effectively bind to PINK1 due to steric hindrance.
- A mutation that alters the "gatekeeper" residue in PINK1 allows for KTP binding and enhances its activity in processes like ubiquitin phosphorylation, indicating a potential pathway for therapeutic development.
Article 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.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10798554 | PMC |
| http://dx.doi.org/10.1126/sciadv.adj7408 | DOI Listing |
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