LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome.
Alanine
/ analogs & derivatives
Aminobutyrates
/ metabolism
Animals
Antimicrobial Cationic Peptides
/ metabolism
Female
Glutathione
/ metabolism
HEK293 Cells
Humans
MAP Kinase Kinase 1
/ metabolism
Male
Membrane Proteins
/ chemistry
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase Kinases
/ metabolism
Phosphate-Binding Proteins
/ chemistry
Phosphorylation
Protein Domains
Proteome
Receptors, G-Protein-Coupled
/ chemistry
Sulfides
/ metabolism
C-glutathionylation
LanCL
MEK1
dehydroalanine
dehydrobutyrine
eliminylome
lanthionine
phosphoThr lyase
protein damage
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
13 05 2021
13 05 2021
Historique:
received:
30
04
2020
revised:
22
01
2021
accepted:
31
03
2021
pubmed:
2
5
2021
medline:
22
12
2021
entrez:
1
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33932340
pii: S0092-8674(21)00436-0
doi: 10.1016/j.cell.2021.04.001
pmc: PMC8209957
mid: NIHMS1690856
pii:
doi:
Substances chimiques
Aminobutyrates
0
Antimicrobial Cationic Peptides
0
LANCL2 protein, mouse
0
Lancl1 protein, mouse
0
Lancl3 protein, mouse
0
Membrane Proteins
0
Phosphate-Binding Proteins
0
Proteome
0
Receptors, G-Protein-Coupled
0
Sulfides
0
dehydrobutyrine
20748-08-7
dehydroalanine
98RA387EKY
MAP Kinase Kinase 1
EC 2.7.12.2
Mitogen-Activated Protein Kinase Kinases
EC 2.7.12.2
Glutathione
GAN16C9B8O
lanthionine
JO78O46X3K
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2680-2695.e26Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR048914
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM079038
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM089771
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027109
Pays : United States
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
Mol Biol Cell. 2014 Dec 1;25(24):3954-61
pubmed: 25273559
EMBO J. 1994 Mar 1;13(5):1123-31
pubmed: 8131746
Mol Cell Proteomics. 2013 Mar;12(3):797-806
pubmed: 23233447
Science. 2007 Feb 16;315(5814):1000-3
pubmed: 17303758
Biochemistry. 2007 Mar 20;46(11):3262-9
pubmed: 17305318
Nature. 2007 Apr 26;446(7139):1105-9
pubmed: 17460675
Nat Protoc. 2007;2(9):2212-21
pubmed: 17853878
J Proteome Res. 2015 Mar 6;14(3):1574-86
pubmed: 25660469
Nat Chem Biol. 2018 Apr;14(4):375-380
pubmed: 29507389
Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10430-5
pubmed: 20479271
Chem Rev. 2017 Apr 26;117(8):5457-5520
pubmed: 28135077
Dev Cell. 2014 Aug 25;30(4):479-87
pubmed: 25158856
J Mol Biol. 1971 Feb 14;55(3):379-400
pubmed: 5551392
Nature. 2014 Mar 27;507(7493):462-70
pubmed: 24670764
Science. 2006 Mar 10;311(5766):1464-7
pubmed: 16527981
Sci Rep. 2017 Jan 20;7:40980
pubmed: 28106097
BMC Cancer. 2010 Aug 23;10:449
pubmed: 20731849
Genes Dev. 2009 Jun 15;23(12):1387-92
pubmed: 19528316
J Biol Chem. 1999 Nov 26;274(48):34029-35
pubmed: 10567369
Biochem J. 1998 Feb 15;330 ( Pt 1):175-9
pubmed: 9461507
BMC Bioinformatics. 2013 Mar 22;14:104
pubmed: 23517090
Elife. 2015 Jul 30;4:
pubmed: 26226635
Chem Rev. 2005 Feb;105(2):633-84
pubmed: 15700960
Nucleic Acids Res. 2015 Jan;43(Database issue):D512-20
pubmed: 25514926
Antioxid Redox Signal. 2010 Jun 1;12(11):1235-46
pubmed: 20070187
Aging Cell. 2014 Apr;13(2):226-34
pubmed: 24134651
Biochemistry. 2009 Mar 31;48(12):2661-74
pubmed: 19161339
Sci Data. 2017 Aug 29;4:170113
pubmed: 28850107
Infect Immun. 2006 Oct;74(10):5964-76
pubmed: 16988276
Chem Commun (Camb). 2015 Sep 11;51(70):13470-3
pubmed: 26219458
Mol Microbiol. 2009 Jan;71(2):350-68
pubmed: 19017275
J Clin Oncol. 2011 Aug 1;29(22):3085-96
pubmed: 21383288
Nat Chem Biol. 2013 Mar;9(3):157-9
pubmed: 23314913
Chem Commun (Camb). 2011 Aug 14;47(30):8623-5
pubmed: 21717004
Mol Cell Proteomics. 2013 Jun;12(6):1709-22
pubmed: 23436904
J Biol Chem. 2013 Sep 13;288(37):26497-504
pubmed: 23861399
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
ACS Cent Sci. 2016 Sep 28;2(9):637-646
pubmed: 27725962
Trends Biochem Sci. 2009 Mar;34(3):108-14
pubmed: 19233656
J Mol Biol. 1999 May 7;288(3):427-39
pubmed: 10329152
Annu Rev Biochem. 1983;52:711-60
pubmed: 6137189
J Proteome Res. 2011 Apr 1;10(4):1794-805
pubmed: 21254760
Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515
pubmed: 30395287
Proc Natl Acad Sci U S A. 1987 May;84(9):2595-9
pubmed: 3472227
Trends Pharmacol Sci. 2012 Dec;33(12):656-68
pubmed: 23121834
J Am Chem Soc. 2011 Sep 14;133(36):14216-9
pubmed: 21848315
Biochim Biophys Acta. 1998 Feb 11;1395(3):301-8
pubmed: 9512664
Nat Immunol. 2007 Jan;8(1):47-56
pubmed: 17159983
Biochem Biophys Res Commun. 2000 Aug 18;275(1):69-74
pubmed: 10944443
Neuro Oncol. 2002 Apr;4(2):86-94
pubmed: 11916499
Chem Biol. 2013 Feb 21;20(2):146-59
pubmed: 23438744
J Mass Spectrom. 2001 Oct;36(10):1083-91
pubmed: 11747101
Free Radic Biol Med. 2011 Jul 1;51(1):197-204
pubmed: 21420488
Mol Cell Proteomics. 2016 Jan;15(1):1-11
pubmed: 26518762
Mol Cell Biochem. 2005 Apr;272(1-2):133-44
pubmed: 16010980
Exp Eye Res. 2004 Oct;79(4):499-512
pubmed: 15381034
Biochemistry. 2018 Jul 3;57(26):3790-3796
pubmed: 29792689
Nature. 2019 Nov;575(7783):505-511
pubmed: 31723265
J Agric Food Chem. 1999 Apr;47(4):1295-319
pubmed: 10563973
Cell. 2010 Dec 23;143(7):1174-89
pubmed: 21183079
EMBO J. 1994 Apr 1;13(7):1610-9
pubmed: 8157000
Gene. 2001 May 16;269(1-2):73-80
pubmed: 11376939
J Biol Chem. 2003 Mar 7;278(10):8118-25
pubmed: 12506122
EMBO Rep. 2014 Jul;15(7):792-800
pubmed: 24778456
ACS Chem Biol. 2015 May 15;10(5):1234-8
pubmed: 25723375
J Biol Chem. 1993 Mar 5;268(7):5097-106
pubmed: 8444886
Methods Enzymol. 2010;474:23-34
pubmed: 20609902
J Ind Microbiol Biotechnol. 2019 Mar;46(3-4):537-549
pubmed: 30484123
Mol Cell Proteomics. 2013 Oct;12(10):2952-68
pubmed: 23828894
J Am Soc Mass Spectrom. 2003 Jun;14(6):593-600
pubmed: 12781460
J Am Chem Soc. 2016 Jul 20;138(28):8678-81
pubmed: 27336299
DNA Seq. 2001;12(3):161-6
pubmed: 11762191
Nature. 2014 May 29;509(7502):575-81
pubmed: 24870542
J Am Chem Soc. 2014 Dec 17;136(50):17513-29
pubmed: 25409537
J Biol Chem. 1997 Apr 25;272(17):11057-62
pubmed: 9110999
Trends Biochem Sci. 2009 Feb;34(2):85-96
pubmed: 19135374
Mol Cell. 2007 Dec 14;28(5):899-913
pubmed: 18060821
Expert Opin Drug Metab Toxicol. 2011 Jul;7(7):891-910
pubmed: 21557709
Biochemistry. 2012 May 29;51(21):4271-9
pubmed: 22574919
J Biol Chem. 2007 Jul 20;282(29):21169-75
pubmed: 17513866