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.
Highlights
Lanthionine-containing peptides or lanthipeptides are ribosomally synthesized and post-translationally modified peptides produced by bacteria (Repka et al, 2017)
We solved the structure of D1–18-LanCL2 (PDB: 6WQ1), which proved more amenable to crystallization than the full-length protein
Its overall structure resembles that of NisC and LanCL1 and is made up of two layers of 14 a helices with a zinc ion binding site located on one side (Figure 1A)
Summary
Lanthionine-containing peptides or lanthipeptides are ribosomally synthesized and post-translationally modified peptides produced by bacteria (Repka et al, 2017). Lanthionines are installed through dehydratase-mediated conversion of Ser/Thr residues in precursor peptides to dehydroamino acids. Intramolecular addition of thiols of cysteines onto the dehydroamino acid residues is mediated by LanC enzymes or LanC-type domains in bifunctional LanM proteins (Repka et al, 2017). Mammalian genomes encode multiple LanC-like proteins (LanCLs) but lack genes encoding an obvious dehydratase ortholog. The structure of human LanCL1 resembles NisC (a bacterial LanC); both structures contain two-layered a helix barrels that bind Zn2+ (Figure 1A) (Li et al, 2006; Zhang et al, 2009).
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