@article{15883da2657b47b4a14c51e011429d03,
title = "LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome",
abstract = "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.",
keywords = "C-glutathionylation, LanCL, MEK1, dehydroalanine, dehydrobutyrine, eliminylome, lanthionine, phosphoThr lyase, protein damage",
author = "Lai, {Kuan Yu} and Galan, {S{\'e}bastien R.G.} and Yibo Zeng and Zhou, {Tianhui Hina} and Chang He and Ritu Raj and Jitka Riedl and Shi Liu and Chooi, {K. Phin} and Neha Garg and Min Zeng and Jones, {Lyn H.} and Hutchings, {Graham J.} and Shabaz Mohammed and Nair, {Satish K.} and Jie Chen and Davis, {Benjamin G.} and {van der Donk}, {Wilfred A.}",
note = "Funding Information: This study was supported by the Howard Hughes Medical Institute (to W.A.V.), NIH GM089771 (to J.C.), NIH GM 079038 (to S.K.N.), the BBSRC with AstraZeneca (S.R.G.G.), the EPSRC UK Catalysis Hub (EP/R026815/1, EP/R026939/1 Y.Z. G.J.H. and B.G.D.), the EU Horizon 2020 Programme under the Marie Sklodowska-Curie program (700124, J.R.), the Felix Foundation (R.R.), and the EPSRC with Pfizer (K.P.C.). A MALDI TOF mass spectrometer was purchased with a grant from the National Institutes of Health (S10 RR027109 A). We thank Dr. Ian R. Bothwell and Dr. Alex V. Ulanov (Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign) for assistance with GC-MS, Elisabete Pires for assistance with MS/MS analysis, Dr. Shih-Hsuan Hsiao (Veterinary Medicine, UIUC) for histopathology of deceased TKO mice, and Drs. J. Read and G. Pairaudeau (AstraZeneca) for useful discussions. K.-Y.L. performed pull-down, peptide activity, and cellular assays; Y.Z. and J.R. performed glutathionylation of MEK-Dha and ERK-Dha; S.R.G.G. K.P.C. R.R. J.R. L.H.J. and G.J.H. developed Dha installation technology; R.R. and S.R.G.G. performed protein MS/MS; T.H.Z. performed unbiased pull-down and mouse tissue analysis; T.H.Z. and M.Z. constructed survival curves; S.L. provided GPX. R.R. B.G.D. and S.M. conducted the eliminylome survey; N.G. and S.K.N. performed crystallography; C.H. performed kinetics with peptides. J.C. B.G.D. and W.A.V. designed the study. K.-Y.L. C.H. J.C. S.R.G.G. B.G.D. and W.A.V. wrote the manuscript; and all authors read and commented on the manuscript. The authors declare no competing interests. Funding Information: This study was supported by the Howard Hughes Medical Institute (to W.A.V.), NIH GM089771 (to J.C.), NIH GM 079038 (to S.K.N.), the BBSRC with AstraZeneca (S.R.G.G.), the EPSRC UK Catalysis Hub ( EP/R026815/1 , EP/R026939/1 Y.Z., G.J.H., and B.G.D.), the EU Horizon 2020 Programme under the Marie Sklodowska-Curie program ( 700124 , J.R.), the Felix Foundation (R.R.), and the EPSRC with Pfizer (K.P.C.). A MALDI TOF mass spectrometer was purchased with a grant from the National Institutes of Health ( S10 RR027109 A ). We thank Dr. Ian R. Bothwell and Dr. Alex V. Ulanov (Roy J. Carver Biotechnology Center, University of Illinois at Urbana-Champaign) for assistance with GC-MS, Elisabete Pires for assistance with MS/MS analysis, Dr. Shih-Hsuan Hsiao (Veterinary Medicine, UIUC) for histopathology of deceased TKO mice, and Drs. J. Read and G. Pairaudeau (AstraZeneca) for useful discussions. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "13",
doi = "10.1016/j.cell.2021.04.001",
language = "English (US)",
volume = "184",
pages = "2680--2695.e26",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "10",
}