Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function.

Autor: Rosier K; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium., McDevitt MT; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Smet J; Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium., Floyd BJ; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Verschoore M; Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium., Marcaida MJ; Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Bingman CA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Lemmens I; Center for Medical Biotechnology, VIB, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium., Dal Peraro M; Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Tavernier J; Center for Medical Biotechnology, VIB, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium., Cravatt BF; The Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA., Gounko NV; VIB-KU Leuven Center for Brain & Disease Research, Electron Microscopy Platform & VIB-Bioimaging Core, Leuven, Belgium.; Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium., Vints K; VIB-KU Leuven Center for Brain & Disease Research, Electron Microscopy Platform & VIB-Bioimaging Core, Leuven, Belgium.; Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium., Monnens Y; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium., Bhalla K; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium., Aerts L; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium., Rashan EH; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA., Vanlander AV; Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium., Van Coster R; Department of Internal Medicine and Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium., Régal L; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.; Department of Pediatrics, Pediatric Neurology and Metabolism, UZ Brussel, Brussels, Belgium., Pagliarini DJ; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.; Morgridge Institute for Research, Madison, WI 53715, USA.; Departments of Cell Biology and Physiology, Biochemistry and Molecular Biophysics, and Genetics, Washington University School of Medicine, St Louis, MO 63110, USA., Creemers JWM; Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
Jazyk: angličtina
Zdroj: IScience [iScience] 2021 Nov 14; Vol. 24 (12), pp. 103460. Date of Electronic Publication: 2021 Nov 14 (Print Publication: 2021).
DOI: 10.1016/j.isci.2021.103460
Abstrakt: 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 PREPL L isoform localizes to mitochondria, whereas PREPL S 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 PREPL L is involved in mitochondrial homeostasis.
Competing Interests: The authors declare no competing interests.
(© 2021 The Author(s).)
Databáze: MEDLINE
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