PINK1 autophosphorylation is required for ubiquitin recognition

EMBO Reports
Shafqat RasoolJean-François Trempe

Abstract

Mutations in PINK1 cause autosomal recessive Parkinson's disease (PD), a neurodegenerative movement disorder. PINK1 is a kinase that acts as a sensor of mitochondrial damage and initiates Parkin-mediated clearance of the damaged organelle. PINK1 phosphorylates Ser65 in both ubiquitin and the ubiquitin-like (Ubl) domain of Parkin, which stimulates its E3 ligase activity. Autophosphorylation of PINK1 is required for Parkin activation, but how this modulates the ubiquitin kinase activity is unclear. Here, we show that autophosphorylation of Tribolium castaneum PINK1 is required for substrate recognition. Using enzyme kinetics and NMR spectroscopy, we reveal that PINK1 binds the Parkin Ubl with a 10-fold higher affinity than ubiquitin via a conserved interface that is also implicated in RING1 and SH3 binding. The interaction requires phosphorylation at Ser205, an invariant PINK1 residue (Ser228 in human). Using mass spectrometry, we demonstrate that PINK1 rapidly autophosphorylates in trans at Ser205. Small-angle X-ray scattering and hydrogen-deuterium exchange experiments provide insights into the structure of the PINK1 catalytic domain. Our findings suggest that multiple PINK1 molecules autophosphorylate first prior to binding an...Continue Reading

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Citations

Apr 24, 2018·The Journal of Physiology·Gilles GouspillouSabah N A Hussain
Sep 22, 2018·Critical Reviews in Biochemistry and Molecular Biology·Shafqat Rasool, Jean-François Trempe
Apr 27, 2019·CNS Neuroscience & Therapeutics·Maribel LuceroJeremy W Chambers
Jul 17, 2019·Proceedings of the National Academy of Sciences of the United States of America·Vinicius M FavaErwin Schurr
Jul 12, 2018·Scientific Reports·Kei OkatsuShuya Fukai
Jun 2, 2020·Frontiers in Cell and Developmental Biology·Liming WangHan-Ming Shen
Jul 4, 2018·Nature Structural & Molecular Biology·Véronique SauvéKalle Gehring
Oct 3, 2018·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Koji Yamano, Michael Lazarou
Jun 30, 2019·Cellular and Molecular Life Sciences : CMLS·Andrew N Bayne, Jean-François Trempe
Mar 12, 2020·Current Genetics·Mohamed A Eldeeb, Mohamed A Ragheb
Jan 14, 2021·The EMBO Journal·Mashun OnishiKoji Okamoto
Dec 30, 2020·The Journal of Biological Chemistry·Emily H ClarkThomas Briston
May 18, 2020·Neuroscience Research·Edgar Djaha Yoboue, Enza Maria Valente
Jan 18, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiao-Le WangYi Zhang
Jan 12, 2021·Frontiers in Neurology·Ziqi ShaoBo Bai
Nov 8, 2020·International Journal of Molecular Sciences·Mauro Agrò, Javier Díaz-Nido
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Apr 5, 2021·Environmental Science and Pollution Research International·Shuhua GuoJianzhu Liu
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Apr 17, 2020·Journal of the American Society for Mass Spectrometry·Kirandeep K DeolEric R Strieter
May 23, 2020·Current Neuropharmacology·Dmitrii M BelousovGjumrakch Aliev

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