Structure of lasso peptide epimerase MslH reveals metal-dependent acid/base catalytic mechanism

The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified peptide (RiPP) consisting of 21 amino acids with D-tryptophan at the C -terminus, and is derived from the precursor peptide MslA. MslH, encoded in the MS-271 biosynthetic gene cluster ( msl ), catalyzes the epime...

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Bibliographic Details
Published in:Nature communications 2023-08, Vol.14 (1), p.4752-4752, Article 4752
Main Authors: Nakashima, Yu, Kawakami, Atsushi, Ogasawara, Yasushi, Maeki, Masatoshi, Tokeshi, Manabu, Dairi, Tohru, Morita, Hiroyuki
Format: Article
Language:English
Subjects:
631/535/1266
639/638/45/173
639/638/45/603
639/638/45/607
639/638/60
Amino acids
C-Terminus
Calcineurin
Crystal structure
Crystallography
Epimerase
Humanities and Social Sciences
Metallography
multidisciplinary
Peptides
Post-translation
Science
Science (multidisciplinary)
Site-directed mutagenesis
Structural analysis
Tryptophan
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Summary:The lasso peptide MS-271 is a ribosomally synthesized and post-translationally modified peptide (RiPP) consisting of 21 amino acids with D-tryptophan at the C -terminus, and is derived from the precursor peptide MslA. MslH, encoded in the MS-271 biosynthetic gene cluster ( msl ), catalyzes the epimerization at the Cα center of the MslA C -terminal Trp21, leading to epi -MslA. The detailed catalytic process, including the catalytic site and cofactors, has remained enigmatic. Herein, based on X-ray crystallographic studies in association with MslA core peptide analogues, we show that MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold. The crystal structure analysis, followed by site-directed mutagenesis, docking simulation, and ICP-MS studies demonstrate that MslH employs acid/base chemistry to facilitate the reversible epimerization of the C- terminal Trp21 of MslA, by utilizing two pairs of His/Asp catalytic residues that are electrostatically tethered to a six-coordination motif with a Ca(II) ion via water molecules. MslH, encoded in the MS-271 biosynthetic gene cluster, catalyzes the epimerization at the Cα center of the MslA C-terminal Trp21, however, the detailed catalytic process was unknown. Here, the authors report MslH is a metallo-dependent peptide epimerase with a calcineurin-like fold.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-40232-x