Interaction of PINK1 with nucleotides and kinetin
- Author(s)
- Gan, ZY; Callegari, S; Nguyen, TN; Kirk, NS; Leis, A; Lazarou, M; Dewson, G; Komander, D;
- Details
- Publication Year 2024-01-19,Volume 10,Issue #3,Page eadj7408
- Journal Title
- Science Advances
- 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.
- Publisher
- AAAS
- Research Division(s)
- Ubiquitin Signalling; Structural Biology
- PubMed ID
- 38241364
- Publisher's Version
- https://doi.org/10.1126/sciadv.adj7408
- Open Access at Publisher's Site
https://doi.org/10.1126/sciadv.adj740- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-01-25 09:17:58
Last Modified: 2024-01-25 10:44:27