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  • 标题:Prolyl endopeptidase-like is a (thio)esterase involved in mitochondrial respiratory chain function
  • 本地全文:下载
  • 作者:Karen Rosier ; Molly T. McDevitt ; Joél Smet
  • 期刊名称:iScience
  • 印刷版ISSN:2589-0042
  • 出版年度:2021
  • 卷号:24
  • 期号:12
  • 页码:1-25
  • DOI:10.1016/j.isci.2021.103460
  • 语种:English
  • 出版社:Elsevier
  • 摘要:SummaryDeficiency 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 PREPLLisoform localizes to mitochondria, whereas PREPLSremains cytosolic.PreplKO mice showed reduced mitochondrial complex activities and disrupted mitochondrial gene expression. Furthermore, mitochondrial ultrastructure was abnormal in a PREPL-deficient patient andPreplKO 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 PREPLLis involved in mitochondrial homeostasis.Graphical abstractDisplay OmittedHighlights•Protein interactors connect PREPL with mitochondrial processes•Deficiency of PREPL results in mitochondrial dysfunction in mice (and patients)•Despite homology with peptidases, PREPL has (thio)esterase activityin vitro•Crystal structure of PREPL supports the substrate specificityMolecular biology; Molecular medicine; Structural biology
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