@article{8bb696813d2f4b77ab1f0950a7d146e5,
title = "Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function",
abstract = "Deficiency of the serine hydrolase prolyl endopeptidase-like (PREPL) causes a recessive metabolic disorder characterized by neonatal hypotonia, feeding difficulties, and growth hormone deficiency. The pathophysiology of PREPL deficiency and the physiological substrates of PREPL remain largely unknown. In this study, we connect PREPL with mitochondrial gene expression and oxidative phosphorylation by analyzing its protein interactors. We demonstrate that the long PREPLL isoform localizes to mitochondria, whereas PREPLS remains cytosolic. Prepl KO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient and Prepl KO mice. In addition, we reveal that PREPL has (thio)esterase activity and inhibition of PREPL by Palmostatin M suggests a depalmitoylating function. We subsequently determined the crystal structure of PREPL, thereby providing insight into the mechanism of action. Taken together, PREPL is a (thio)esterase rather than a peptidase and PREPLL is involved in mitochondrial homeostasis.",
keywords = "Molecular biology, Molecular medicine, Structural biology",
author = "Karen Rosier and McDevitt, {Molly T.} and Jo{\'e}l Smet and Floyd, {Brendan J.} and Maxime Verschoore and Marcaida, {Maria J.} and Bingman, {Craig A.} and Irma Lemmens and {Dal Peraro}, Matteo and Jan Tavernier and Cravatt, {Benjamin F.} and Gounko, {Natalia V.} and Katlijn Vints and Yenthe Monnens and Kritika Bhalla and Laetitia Aerts and Rashan, {Edrees H.} and Vanlander, {Arnaud V.} and {Van Coster}, Rudy and Luc R{\'e}gal and Pagliarini, {David J.} and Creemers, {John W.M.}",
note = "Funding Information: We would like to thank Andrew G. Engel for re-evaluating the electron micrographs of the PREPL-deficient patient, Sandra Meulemans for technical assistance, and Laetitia Aerts and Kevin Martens for help with the mouse studies. We thank Pieter Baatsen for his advice on the EM analysis. We thank members of the UW-Madison-based Mitochondrial Protein Partnership for their assistance in PREPL purification and crystallization, including David J. Aceti, Russell L. Wrobel, Ronnie Frederich, Emily T. Beebe, Tina M. Misenheimer, Robert W. Smith, and Zsolt Zolnai. We would like to thank Bryan Dickinson and his group for their guidance. M.J.M. thanks L. Abriata, A. Theodoropoulou, and M. Moncrieffe for helpful discussions. The graphical abstracts were created with BioRender.com . This work was supported by FWO Vlaanderen (grant number G0B9119N ), KU Leuven C1 (grant number C14/16/070 ). D.J.P. was supported by the National Institutes of Health grants U01GM094622 and R35GM131795 , and funds from the BJC Investigator Program. C.A.B. thanks Craig Ogata and the entire GM/CA staff for technical assistance during diffraction data collection. GM/CA@APS has been funded by the National Cancer Institute ( ACB-12002 ) and the National Institute of General Medical Sciences ( AGM-12006 , P30GM138396 ). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = dec,
day = "17",
doi = "10.1016/j.isci.2021.103460",
language = "English",
volume = "24",
journal = "iScience",
issn = "2589-0042",
number = "12",
}