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  • Fiesel, Fabienne C.Mayo Clinic Florida (author)

Substitution of PINK1 Gly411 modulates substrate receptivity and turnover

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2022-12-05
  • Informa UK Limited,2023

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:dbf6a10f-63ad-4c16-afb5-bf67f929dd88
  • https://lup.lub.lu.se/record/dbf6a10f-63ad-4c16-afb5-bf67f929dd88URI
  • https://doi.org/10.1080/15548627.2022.2151294DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • The ubiquitin (Ub) kinase-ligase pair PINK1-PRKN mediates the degradation of damaged mitochondria by macroautophagy/autophagy (mitophagy). PINK1 surveils mitochondria and upon stress accumulates on the mitochondrial surface where it phosphorylates serine 65 of Ub to activate PRKN and to drive mitochondrial turnover. While loss of either PINK1 or PRKN is genetically linked to Parkinson disease (PD) and activating the pathway seems to have great therapeutic potential, there is no formal proof that stimulation of mitophagy is always beneficial. Here we used biochemical and cell biological methods to study single nucleotide variants in the activation loop of PINK1 to modulate the enzymatic function of this kinase. Structural modeling and in vitro kinase assays were used to investigate the molecular mechanism of the PINK1 variants. In contrast to the PD-linked PINK1G411S mutation that diminishes Ub kinase activity, we found that the PINK1G411A variant significantly boosted Ub phosphorylation beyond levels of PINK1 wild type. This resulted in augmented PRKN activation, mitophagy rates and increased viability after mitochondrial stress in midbrain-derived, gene-edited neurons. Mechanistically, the G411A variant stabilizes the kinase fold of PINK1 and transforms Ub to adopt the preferred, C-terminally retracted conformation for improved substrate turnover. In summary, we identify a critical role of residue 411 for substrate receptivity that may now be exploited for drug discovery to increase the enzymatic function of PINK1. The genetic substitution of Gly411 to Ala increases mitophagy and may be useful to confirm neuroprotection in vivo and might serve as a critical positive control during therapeutic development. Abbreviations: ATP: adenosine triphosphate; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; Ub-CR: ubiquitin with C-terminally retracted tail; CTD: C-terminal domain (of PINK1); ELISA: enzyme-linked immunosorbent assay; HCI: high-content imaging; IB: immunoblot; IF: immunofluorescence; NPC: neuronal precursor cells; MDS: molecular dynamics simulation; PD: Parkinson disease; p-S65-Ub: ubiquitin phosphorylated at Ser65; RMSF: root mean scare fluctuation; TOMM: translocase of outer mitochondrial membrane; TVLN: ubiquitin with T66V and L67N mutation, mimics Ub-CR; Ub: ubiquitin; WT: wild-type.

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  • Fričová, DominikaMayo Clinic Florida (author)
  • Hayes, Caleb S.Mayo Clinic Florida (author)
  • Coban, Mathew A.Mayo Clinic Florida (author)
  • Hudec, RomanMayo Clinic Florida (author)
  • Bredenberg, Jenny M.Mayo Clinic Florida (author)
  • Broadway, Benjamin J.Mayo Clinic Florida (author)
  • Markham, Briana N.Mayo Clinic Florida (author)
  • Yan, TingxiangMayo Clinic Florida (author)
  • Boneski, Paige K.Mayo Clinic Florida (author)
  • Fiorino, GabriellaMayo Clinic Florida (author)
  • Watzlawik, Jens O.Mayo Clinic Florida (author)
  • Hou, XuMayo Clinic Florida (author)
  • McCarty, Arthur M.Mayo Clinic Florida (author)
  • Lewis-Tuffin, Laura J.Mayo Clinic Florida (author)
  • Zhong, JunMayo Clinic Minnesota (author)
  • Madden, Benjamin J.Mayo Clinic Minnesota (author)
  • Ordureau, AlbanMemorial Sloan-Kettering Cancer Center,Harvard Medical School (author)
  • an, HeeseonHarvard Medical School,Memorial Sloan-Kettering Cancer Center (author)
  • Puschmann, AndreasLund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk neurogenetik,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Neurogenetics,Lund University Research Groups(Swepub:lu)med-aps (author)
  • Wszolek, Zbigniew K.Mayo Clinic Florida (author)
  • Ross, Owen A.Mayo Clinic Florida (author)
  • Harper, J. WadeHarvard Medical School (author)
  • Caulfield, Thomas R.Mayo Clinic Florida (author)
  • Springer, WolfdieterMayo Clinic Florida (author)
  • Mayo Clinic FloridaMayo Clinic Minnesota (creator_code:org_t)

Related titles

  • In:Autophagy: Informa UK Limited19:6, s. 1711-17321554-86271554-8635

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