Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function
Summary: 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 large...
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Elsevier
2021
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oai:doaj.org-article:a2916c2ecc194c18bb66fc5774a5e60f2021-11-28T04:36:51ZProlyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function2589-004210.1016/j.isci.2021.103460https://doaj.org/article/a2916c2ecc194c18bb66fc5774a5e60f2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2589004221014310https://doaj.org/toc/2589-0042Summary: 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.Karen RosierMolly T. McDevittJoél SmetBrendan J. FloydMaxime VerschooreMaria J. MarcaidaCraig A. BingmanIrma LemmensMatteo Dal PeraroJan TavernierBenjamin F. CravattNatalia V. GounkoKatlijn VintsYenthe MonnensKritika BhallaLaetitia AertsEdrees H. RashanArnaud V. VanlanderRudy Van CosterLuc RégalDavid J. PagliariniJohn W.M. CreemersElsevierarticleMolecular biologyMolecular medicineStructural biologyScienceQENiScience, Vol 24, Iss 12, Pp 103460- (2021) |
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DOAJ |
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EN |
| topic |
Molecular biology Molecular medicine Structural biology Science Q |
| spellingShingle |
Molecular biology Molecular medicine Structural biology Science Q Karen Rosier Molly T. McDevitt Joél Smet Brendan J. Floyd Maxime Verschoore Maria J. Marcaida Craig A. Bingman Irma Lemmens Matteo Dal Peraro Jan Tavernier Benjamin F. Cravatt Natalia V. Gounko Katlijn Vints Yenthe Monnens Kritika Bhalla Laetitia Aerts Edrees H. Rashan Arnaud V. Vanlander Rudy Van Coster Luc Régal David J. Pagliarini John W.M. Creemers Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| description |
Summary: 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. |
| format |
article |
| author |
Karen Rosier Molly T. McDevitt Joél Smet Brendan J. Floyd Maxime Verschoore Maria J. Marcaida Craig A. Bingman Irma Lemmens Matteo Dal Peraro Jan Tavernier Benjamin F. Cravatt Natalia V. Gounko Katlijn Vints Yenthe Monnens Kritika Bhalla Laetitia Aerts Edrees H. Rashan Arnaud V. Vanlander Rudy Van Coster Luc Régal David J. Pagliarini John W.M. Creemers |
| author_facet |
Karen Rosier Molly T. McDevitt Joél Smet Brendan J. Floyd Maxime Verschoore Maria J. Marcaida Craig A. Bingman Irma Lemmens Matteo Dal Peraro Jan Tavernier Benjamin F. Cravatt Natalia V. Gounko Katlijn Vints Yenthe Monnens Kritika Bhalla Laetitia Aerts Edrees H. Rashan Arnaud V. Vanlander Rudy Van Coster Luc Régal David J. Pagliarini John W.M. Creemers |
| author_sort |
Karen Rosier |
| title |
Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| title_short |
Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| title_full |
Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| title_fullStr |
Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| title_full_unstemmed |
Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| title_sort |
prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/a2916c2ecc194c18bb66fc5774a5e60f |
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