LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome
| Autor: | Ritu Raj, Wilfred A. van der Donk, Kuan Yu Lai, Neha Garg, Satish K. Nair, Shabaz Mohammed, Jie Chen, Benjamin G. Davis, Sébastien R. G. Galan, Graham J. Hutchings, Min Zeng, Chang He, Jitka Riedl, Yibo Zeng, Tianhui Hina Zhou, K. Phin Chooi, Shi Liu, Lyn H. Jones |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Proteome Antimicrobial peptides MAP Kinase Kinase 1 Biology Sulfides General Biochemistry Genetics and Molecular Biology Article Receptors G-Protein-Coupled 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Protein Domains Dehydroalanine Animals Humans Phosphorylation 030304 developmental biology chemistry.chemical_classification Mice Knockout Mitogen-Activated Protein Kinase Kinases 0303 health sciences Alanine Kinase Aminobutyrates Membrane Proteins Glutathione Phosphate-Binding Proteins Enzyme HEK293 Cells chemistry Biochemistry Nucleic acid Female 030217 neurology & neurosurgery Antimicrobial Cationic Peptides |
| Zdroj: | Cell |
| ISSN: | 1097-4172 0092-8674 |
| Popis: | Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such "elimination damage" generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically. |
| Databáze: | OpenAIRE |
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